Human-Immunodeficiency Virus: Infection, Immunity, and ...
Doc File 82.00KByte
Human-Immunodeficiency Virus: Infection, Immunity, and Treatment
15 September 2004
Research sponsored by DARPA Grant DAAD19-02-1-0288, P00001
Factors leading to the emergence of the human-immunodeficiency virus (HIV) in humans are unknown. HIV was first isolated in 1959 from an African male (Nahmias et al. 1986, Levy). In the last 45 years, several subtypes, or clades, of HIV have been identified including the most common, HIV-1, and the less common HIV-2. There are currently three groups of HIV-1 isolates: M, N, and O. Isolate M, the major strain, consists of at least ten clades, A through J, wherein B is most common in Europe and North America and A, C, D in Africa, with C being the most widespread (web a). HIV-2 has similar symptoms to and appears closely related to the simian and feline lentiviruses SIV and FIV, respectively (Marlink 1996, Levy). The close similarity between HIV-2 and SIV has lead many investigators to believe that HIV originated from primates (Marlink 1996, Levy). However, the existence of distinct clades of HIV raises difficult questions concerning HIV’s origin; namely whether HIV was introduced by multiple transfers between primates and humans, or if distinct clades of HIV can be explained by evolution from either a common primate derived virus or a common ancestor between primates and humans 600 to 1200 years ago (Eigen et al. 1990, Meyers 1994, Levy).
HIV belongs to the lentivirus genus of the Retroviridae family (Levy). HIV infection develops into the disease AIDS (acquired immuno-deficiency virus), a clinical syndrome characterized by a marked reduction in CD4+ lymphocytes and the frequent development of infections or cancers (Levy). HIV binds to CD4 molecules in order to invade and infect CD4+ T cells. As the disease progresses, the number of CD4+ T cells declines from its normal level of about 1000 per microliter to as low as 400 per microliter, effectively diminishing the patient’s ability to mount an immune response such that the patient eventually dies from an opportunistic infection (web b). For these reasons, CD4+ lymphocyte immunity has served as a main target of research into HIV treatments and vaccines. However, investigations into the role of innate immunity in defending against HIV infection are gaining popularity. The role of cell-mediated immunity and pathways linking the innate and adaptive immune systems are also becoming prime areas of research for preventative and therapeutic treatments.
In this paper the facets of HIV transmission will be discussed, with special attention given to the biochemical and genetic characteristics of HIV and its mode of replication and infection, the host immune response, transmission of HIV, and finally, current treatments and vaccines for HIV. To date, a total of 60 million people have been infected with HIV, 2.2 million of whom have died (Estcourt et al. 2004, UNAIDS). While transmission of HIV and its development to AIDS has been considerably reduced in the US and Europe, an HIV pandemic is spreading throughout Africa, Asia, and much of the third world. Modern technology in the last 25 years has progressed enormously in its ability to detect viral particles and design anti-viral agents. However, such technology is not readily available to the most affected areas and in many cases medical treatment is not culturally accepted. Further, problems encountered in controlling the spread of HIV, merely reflect its manner of transmission, as sexually transmitted diseases are not controllable.
I. HIV: Biochemistry, Genetics, and Mechanism of Infection
Electron microscopy (EM) images of the mature HIV-1(2) virion reveal a cone-shaped core consisting of the viral p24(25) Gag protein (Levy). Inside this capsid or nucleoid structure are two identical strands of RNA 9.8 kb in length that contain multiple ORFs and are closely associated with the viral RNA-dependent DNA Polymerase Pol (RT) and nucleocapsid proteins p9 and p6. HIV’s primary full length mRNA transcript is translated into Gag, Pol, and Env precursor proteins. The Gag precursor is cleaved by viral protease to give rise to capsid (CA, p24), matrix (MA, p17), nucleocapsid (NC, p9), and p6. The Pol precursor protein is cleaved to the viral enzymes RT, protease, and integrase (Göttlinger et al. 2001, Levy). The Env precursor gives rise to viral envelope proteins gp120 and gp41. There are numerous accessory HIV gene products that affect assembly, budding, and infectivity and include Vif, Vpr and Vpu(x) (Levy).
HIV-1 assembles on the plasma membrane of the host cell and is released by budding from the cell surface. In the early stages of HIV-1 virion assembly, myristylated Gag precursor molecules associate in a patch on the inner leaflet of the host plasma membrane (Göttlinger et al. 2001). Precursor Gag molecules are continuously added to form a stable spherical structure called the immature capsid, which protrudes from the cell surface and eventually pinches off to release an immature viral particle into the extracellular environment.
To become infectious, the immature viral particle must undergo a maturation step, which involves a series of proteolytic processing events within the Gag and Pol proteins (Göttlinger et al. 2001). Virus maturation considerably reduces the stability of the viral capsid and makes it susceptible to uncoating, or the stripping away of the outer layers of the viral coat to expose its interior and facilitate replication. Gag cleavage products then condense around the viral genome, giving a characteristic conical core appearance to the mature HIV-1 virion (Levy). The Gag cleavage product MA has a charged and myristoylated N-terminus that confers high membrane affinity and associates with the inner surface of the viral lipid envelope by interacting with phospholipid head groups (Levy, Göttlinger et al. 2001, Bryant & Ratner 1990).
The surface of the mature virion is composed of highly glycolsylated trimeric complexes of the envelope glycoproteins gp120 and gp41 (Levy). Upon infection, gp120 binds to host cell CD4 receptors and undergoes a major conformational change and subsequent proteolysis, resulting in the exposure of binding sites for cellular coreceptors CCR5 or CXCR4 on the viral fusion peptide gp41 (Cormier & Dragic 2000). Consequently, fusion is induced between the virion and host cell membranes and the virus enters the cell. Although the exact mechanism of virus: cell membrane fusion remains a mystery, it is known to be dependent on the cleavage of gp120. It is unknown whether transmission between host cells and infected cells occurs through a similar mechanism, although preliminary trials in macaques suggest that both mechanisms are dependent on cleavage of gp120 (Estercourt et al. 2004, Moore et al. 2001).
Upon entry of HIV into the cell, viral RNA is copied into DNA and the proviral genome is transported to the nucleus and integrated into the host cell genome (Karn 2000). Once integrated into the host chromosome, the virus is subject to regulation by cellular transcription factors, as well as its own regulatory proteins. Such processes are executed by three enzymes on the HIV Pol precursor, which display distinct activities at different stages of the virus. The RNA-dependant DNA Polymerase acts early in replication to form a double-stranded DNA copy (cDNA) of the virus DNA (Levy). Integrase then functions inside the nucleus of the host cell to integrate the viral cDNA into the host chromosomal DNA. HIV DNA is then transcribed to RNA, which reenters the cytosol and is translated by host ribosomes. Finally, protease acts during maturation of the viral particle at the cell surface or in the budding virion to process Gag and Pol polyproteins (Levy). These HIV encoded enzymes are major targets for antiviral therapies and will be discussed further in the treatment section.
HIV encoded RNA binding proteins regulate the interaction of the virion with cellular proteins and are vital for infectivity. The three major viral RNA binding proteins are Tat, Rev, and Nef. Tat (transactivating protein) interacts with the Tat-responsive element, an RNA loop in the 3’ viral long terminal repeat, and acts to upregulate HIV replication and transcription (Levy, Karn 2000). Rev (regulator of viral protein expression) interacts with the cis-acting RNA loop of the Rev-responsive element and is localized to viral envelope mRNA (Levy). Rev appears to affect the function of the spliceosome by controlling the relative amounts of unspliced, singly, and multiply spliced mRNAs. In an infected cell, Rev interacts with cellular proteins as a multimer to permit unspliced mRNA to enter the cytoplasm from the nucleus and to give rise to full length viral proteins needed for progeny production. Rev can also function as a negative regulator, as production of Rev in the late phase of viral replication down-regulates Rev, Tat, and Nef expression. Nef (negative factor) is abundantly produced early in viral gene expression and stimulates viral growth in cell culture and in vivo (Piguet & Trono 1999). Nef downregulates CD4 by interfering with components of the trafficking machinery to redirect CD4 from the trans-Golgi network (TGN) to the endosomal compartment and finally the lysosome for degradation (Piguet & Trono 1999). Currently, vaccines directed against Tat, Rev, and Nef are being tested.
II. Host Immune Response: Innate and Adaptive Immune Response
HIV is infectious as a free virus or in association with virus-infected cells (Levy et al. 2003). To prevent and control an infection, the host must defend itself against both forms of the virus. Existing o fulfill such functions are the innate and adaptive immune response. The innate immune response is rapid, occurring from within minutes to days after, whereas the adaptive immune response is delayed, taking days to weeks. Generally, the innate immune response reacts to patterns, such as conserved microbial motifs, whereas the adaptive immune system reacts to specific epitopes and retains a memory such that it can react rapidly upon a second challenge by the same agent (Levy et al. 2003). Difficulties are encountered in both systems, wherein the innate immune response must discriminate between pathogen and self with a restricted number of receptors and the adaptive immune system is challenged by the tendency of pathogens to mutate.
The innate immune response is the first line of defense against infectious disease and microbial infection. It is imperative to the survival of the host to detect foreign pathogens and commence a defensive response as rapidly as possible. The delay of the innate response is crucial in determining the progression of the virus during early stages of infection, as HIV can be transmitted through genital epithelial tissues in less than 4 hours and to the regional lymph nodes in less than two days (Lehrer 2003). The major players in the innate immune response are the antigen-presenting cells (APCs) and include interferon producing cells (IPCs), natural killer (NK) cells, gamma-delta (γδ) T cells, Langerhans cells, macrophages and dendritic cells (DCs). For the most part, these cell types are present in high numbers in vaginal, foreskin, and oral epithelia. The complement system, pathogen associated molecular patterns (PAMPs) such as toll-like receptors, and soluble factors with antiviral properties, such as chemokines, cytokines, and other small molecules (interferons, interleukins, complement, mannose-binding lectins), are also believed to play an important role in innate immunity (Levy).
HIV-1 can only enter cells expressing the transmembrane protein CD4 found on helper T cells and a second coreceptor, CCR5 or CXCR4 (web b). Strains of HIV-1 designated R5 bind the coreceptor CCR5, whereas strains of HIV-1 designated X4 bind the coreceptor CXCR4. HIV primarily infects CD4+ lymphocytes but also infects other cell types such as macrophages, DCs, and IPCs (Soumelis et al. 2002).
The innate immune system gives rise to soluble factors with antiviral properties such as cytokines, chemokines, and interferons. These factors are known to enhance the innate response of NK cells, MHC expression on target cells, lymphocyte response, and antigen presentation by APC’s (Levy et al. 2003). The CC chemokines RANTES (Regulated on Activation, Normal T Expressed and Secreted), and macrophage inflammatory proteins (MIP) 1-α and 1-β are produced by activation of CD8+ cells, macrophages, DC, NK, and γδ T cells (Lehrer 2003). Soluble chemokines are responsible for attracting monocytes, DCs, T cells and B cells to the site of infection (Lehrer 2003, Levy et al. 2003). There is evidence that raised levels of CC chemokines decrease CCR5 co-receptor surface expression and act to block HIV infection in vitro and SIV infection in vivo (Lehner 2003, Lehner et al. 2000, Lehner et al. 1996, Cocchi et al. 1995,)
IPCs exert an anti-HIV response by secreting type-1 interferons and the cytokines IL-4, IL-5, and IL-10 (Levy et al 2003). Type-1 interferons have been shown to directly inhibit HIV replication in vitro and in vivo (Soumelis et al. 2002, Yamamoto et al. 1986, Hartshorn et al. 1987). Purified IPCs produce 200-1000 times more interferon than other cells in response to microbial infection (Levy et al. 2003). Interleukins help to boost the production and activity of T-cells (CD4+ and CD8+), B-cells, macrophages, and NK cells. The number of IPCs per microliter of blood decreases with the advancement of AIDS, suggesting that loss of circulating IPCs correlates with a high viral load and the occurrence of opportunistic infections (Soumelis et al. 2002, Soumelis et al. 2001, Levy et al. 2003, Feldman et al. 2001). The finding that long-term survivors typically have higher numbers of IPCs than healthy controls further supports the theory that IPCs play an advantageous role in preventing the onset of disease.
The complement system plays an important role in innate immunity and is triggered by the binding of antibody to its antigen. The complement system consists of some 30 proteins circulating in blood plasma, which remain inactive until cleaved by a protease and are subsequently converted to a protease (web b). Activated complement proteins then act to directly lyse the viral particle (web b, Levy et al. 2003). Additionally, the surface of many host cells display mannose binding lectins (MBLs), which bind glycolsylated residues on the HIV-1 envelope to enhance viral phagocytosis and destruction by macrophages, or, in the presence of complement, to directly lyse the virus (Levy et al. 2003). Low levels of MBLs and MBL promoter polymorphisms are associated with an increased risk of HIV-1 infection, rapid AIDS progression, and a shorter survival period after diagnosis (Levy et al. 2003, Garred et al. 1997, Bonitto et al. 2000).
Humans evolved to posses a variety of receptors called pathogen associated molecular patterns, which recognize conserved motifs on pathogens not found in higher eukaryotes (Aderim & Ulevitch 2000). Pathogen associated motifs include mannas on the yeast cell wall, formylated peptides and bacterial cell wall components such as lipopolysaccaride (LPS), lipopeptides, peptidoglycans, and teichoic acids. During the innate immune response, intracellular signaling pathways are activated by pattern recognition receptors on the surface of antigen presenting cells (Levy et al. 2003). Toll-like receptors (TLRs), a PAMP subtype, react with ligand and initiate a cascade of processes leading to the activation of NF-κ-B, the induction of cytokines, and a variety of immune responses. TLRs, originally described in Drosphilia, respond to a variety of stimuli including gram-negative and gram-positive bacteria, double stranded RNA, and oligodeoxynucleotides (Levy et al. 2003). A better understanding how TLR expression and activation are regulated may provide insight into the mechanisms of HIV transmission and pathogenesis. Many believe that TLRs are the crucial link between innate and adaptive immunity and may be potentially exploitable in the design of new therapeutic agents.
The adaptive immune system can respond to antigen by two main mechanisms: antibody-mediated immunity and cell-mediated immunity (web b). In antibody or humoral-mediated immunity, antibodies dissolved in blood, lymph, and other body fluids bind the antigen and trigger a response. In cell-mediated immunity, T cells bind to the surface of other cells that display the antigen and trigger a response, involving other lymphocytes or white blood cells.
The adaptive immune system is primarily composed of lymphocytes from the B and T cell lineages. B cells are produced and mature in the bone marrow, whereas T cells leave the bone marrow to mature in the thymus (web b). Each B cell and T cell is specific for a particular antigen. There are two main categories of T cells characterized by the presence of one of two glycoproteins, CD4 or CD8, which determine what cell types it can bind. CD8+ T cells bind epitopes of the class I histocompatibility molecules whereas CD4+ T cells bind epitopes of the class II histocompatibility molecules. Specialized antigen-presenting cells, such as DCs and macrophages, express class II molecules.
CD4+ T cells, or helper T cells, are essential for both the cell-mediated and antibody-mediated branches of the immune system (web b). CD4+ T cells bind to antigen presented by APCs and then releases chemokines to attract other cells to the area, resulting in an inflammatory response and the accumulation of cells and molecules to destroy the antigenic material. CD4+ cells then bind to antigen presented by B cells. As a result, clones of plasma cells secreting antibodies against the antigenic material are produced.
The best understood CD8+ T cells are cytotoxic T lymphocytes (CTLs), which secrete chemokines that destroy the cell to which they have bound (Wagner et al. 1998, Estcourt et al. 2004). Induction of CTLs triggers a cell-mediated immune response and results in the induction of apoptosis in HIV-infected cells to effectively limit the production of new HIV virions (Estcourt et al. 2004). CTLs cannot prevent the first wave of cell free HIV infection, but, once activated by APCs, can prevent HIV from entering cells in vitro (Estcourt et al. 2004, Wagner et al. 1998). Thus, CTLs can play a role in delaying AIDS development. However, CTLs exert a selective pressure and can allow untargeted HIV variants to overgrow and escape control (Estcourt et al. 2004).
III. Transmission of HIV
Successful viral transmission involves the interaction between virus and cell surface receptor and the penetration of the viral nucleocapsid through the cell membrane and into the cell. The efficacy of HIV transmission is affected by both the number of free HIV particles and the number of HIV-infected cells. The number of virus-infected cells as compared to free virus particles is found to be higher in blood, semen, vaginal fluid, breast milk, and saliva (Levy). HIV detected in blood is found to infect CD4+ T cells and peripheral mononuclear blood cells (PMBCs). Generally, viral titers are very high during the initial acute primary infection and then decrease after a few weeks of infection to the low levels observed in healthy asymptomatic persons and long-term survivors (Levy, Cao et al. 1995). Viral titers typically rise again to high levels during the development of AIDS and in individuals with low CD4+ T cell counts.
There is an increased risk of HIV transmission among IV Drug users, homosexual men, and highly sexually active persons (Levy). There is also a high risk of infection for blood transfusion recipients, hemophiliacs, and newborns of HIV positive mothers. The risk of HIV transmission for all these groups has decreased significantly due to successful needle exchange programs, condom use/ safe sex education, technology for detecting infections and HIV particles in blood, and antiviral therapies. Increased education and availability of sterile needles and syringes has dramatically reduced HIV transmission among IV users. Between 1970 and 1983 blood donations were not screened for HIV, and as a result, by 1982, many transfusion recipients and 50% of hemophiliacs were HIV positive (Levy, Goedert et al. 1989). Hemophiliacs are at an increased risk of HIV infection because they receive multiple preparations of clotting factor over the course of their lifetime. Increased technology for screening HIV in blood samples has reduced the risk of transmission to 1 in 450,000 - 660,000 (Levy, Lackritz et al. 1995, Schreiber et al. 1996).
HIV is transmissible through blood, seminal fluid, vaginal fluid, and breast milk. Infectious HIV is rarely detected in other bodily fluids such as saliva, sweat, bronchoalveolar lavage fluids, synovial fluid, feces, and tears (Levy). Statistics acquired from genital fluids in infected individuals are variable and limited by sample size and demographic representation. In males, HIV infected cells have been found in the urethra, prostrate, otreglans, and testes (Levy, Lecatsas et al. 1985). Infectious virus was reported in 10-30% of seminal fluid samples from HIV positive men. The highest levels of infectious virus in semen were observed in males in the preliminary acute phase, with AIDS, and/or low CD4+ T cell counts (Levy, Vernazza et al. 1994). In women, HIV-infected cells can be found in the secretory glands of the vagina and cervix, the transfer zone of the glandular epithelia, the uterine cavity, as well as cells in menstrual blood (Levy, Nuovo et al. 1993). However, vaginal fluid rarely contains infectious HIV as it was found in only 28% of cervico-vaginal secretions of infected women (Levy, Nielsen et al. 1996). Higher viral titers have been reported in pregnant women, and women with cervical ectopy, abnormal discharge, vitamin A deficiency, or taking oral contraceptives (Levy, John et al. 1997).
In sexual transmission, the receptive partner is at a higher risk of infection. In a heterosexual couple the male to female infection rate is 2-5 times higher than in female to male (Levy, De Vincenzi et al. 1992). If occurring combination with an STD, increased HIV transmission is predicted, as HIV transmission has been found to increase in combination with herpes virus by facilitating infection of keratinocytes. If in combination with treatment for an STD, viral titers generally decrease.
Infectious HIV from an infected mother has been found to transfer through breast milk to the newborn. HIV-1 core antigen has been found in 24% of milk samples in days of/after delivery, but none in subsequent days (Levy, Ruff et al. 1994). Further, RT-PCR detected HIV RNA in 58% of milk samples from 100 infected African women. Low CD4+ cell counts and Vitamin A deficiency were also found to associate with increased virus in breast milk (Levy, Nduati et al. 1995). There is an even greater risk of transmission if mother becomes newly infected after birth, causing an acute increase in viral titer in combination with the lack of maternal antiviral response (Levy, Dunn et al. 1992).
IV. Drug Treatment and Vaccine Development
In recent years a number of therapeutic antiviral agents and increased diagnostic capabilities have been developed, which have greatly improved the quality and length of life for those with access to adequate medical treatment. One common type of treatment, Highly Active Antiretroviral Therapy or HAART, has markedly reduced progression of the disease in the United States and Europe and involves the combination of three or more drugs (web b). The most common classes of drugs used to treat HIV infections are reverse transcription inhibitors, protease inhibitors, and fusion inhibitors.
Reverse transcriptase inhibitors act as nucleoside analogs, wherein they are taken up by cells and incorporated into the growing DNA strand to effectively halt DNA synthesis (web b). Examples include azidothymidine (AZT)(Retrovir®), lamivudine (Epivir®), and didanosine (Videx®). Protease inhibitors block viral protease such that proteins needed to assemble new viruses cannot be cleaved from the large protein precursor. Examples include indinavir (Crixivan®), saquinavir (Invirase®), and ritonavir (Norvir®) (web b). Antiviral drugs such as RT and protease inhibitors have been effective in reducing plasma viremia to undetectable levels in many HIV patients (Levy). Fusion inhibitors interfere with the allosteric change in gp41 that enable virus: host cell membrane fusion (web b). Enfuvirtide, a synthetic polypeptide containing 36 of the amino acids in the fusion domain of gp41, interferes with this process, most likely by through a competitive mechanism. Enfuvirtide (Fuzeon®) has shown promise in phase III clinical trials (web b).
Death rates due to HIV-1 infection have decreased significantly since the development of specific inhibitors of viral enzymes (Cormier & Dragic 2000). The drugs are so expensive ($7,000 to $10,000 per year) that they drain resources in even the most affluent countries, and are simply unavailable to many poor countries where the epidemics rage. With over a dozen drugs or cocktails on the market to target these enzymes, a significant percentage (approximately 25%) of individuals cannot tolerate them (Cormier & Dragic 2000). There is considerable worry about the long-term side effects of these drugs, including nausea, diarrhea, and liver damage (Cormier & Dragic 2000). There is further concern that particularly virulent cocktail resistant HIV isolates will emerge (Cormier & Dragic 2000). Such fears emphasize the need to identify new classes of antiviral drugs that can supplement or partially replace existing drug cocktails (Cormier & Dragic 2000).
Over two dozen experimental anti-HIV vaccines have been developed and clinical trials of some of these have been, and are presently being, undertaken (web b, Korber 2003). Most of these vaccines are designed to induce antibody production against one or more specific viral proteins, and, for the most part, have had disappointing results. HIV has developed a number of mechanisms to escape the antiviral immune response and to persist long-term (Emini & Koff 2004). Numerous antibody-mediated vaccines have been developed which bind to and neutralize viral envelope proteins gp120 and gp41. However, the most essential components of these proteins for interaction with host cells are structurally buried and inaccessible to antibody (Emini & Koff 2004, Wyatt et al. 1998). Additionally, the high error rate of the viral reverse transcriptase leads to the rapid occurrence of mutations and consequentially, an increase in a patient’s viral genetic diversity over time (web b, Emini & Koff 2004). Such a process leads to anti-viral drug resistance and the emergence of new strains of HIV in the human population, making antibody design extremely challenging, as intra- and inter-subtype sequences are extremely variable, as high as 20% and 35%, respectively (Estcourt et al. 2004). Researchers have attempted to handle the complexity of this problem in a variety of ways, such as making cocktails of immunogens from two or three common clades or making immunogens against conserved or average sequences (Estcourt et al. 2004). Some success has been observed using cocktails of neutralizing antibodies against gp120 and gp41 in preventing vaginal or oral mucosal infection with SHIV and HIV (Lehrer 2003, Emini & Koff 2004, Burton et al. 2004). However, the high variability in such proteins renders such an approach unsuitable for a vaccine, which must be broadly active against many viral isolates.
Although decreased viral load and containment of HIV is a reasonable short-term objective for vaccination, long-term and total prevention of infection is the ultimate goal (Lehrer 2003). However, as no HIV-positive individual has ever been known to clear HIV infection once established, the notion of ‘protective immunity’ against HIV is an oxymoron, as it may not exist (Korber 2003). Despite such sobering reminders, vaccine research is being conducted around the globe utilizing a variety of strategies. The most popular strategies towards preventative immunization against HIV include the production of neutralizing antibodies, as described above, the induction of cell-mediated responses, the induction of mucosal immunity, and DNA vaccination (Lehner 2003). Vaccines are frequently delivered with the addition of an adjuvant, usually a microbial derived protein or molecule, which alerts the host immune system through a PAMP triggered mechanism (Jiang & Koganty 2003).
A number of vaccines have been designed to favor the development of cell-mediated immunity by cytotoxic T cells, which target and kill cells expressing viral antigens (Lehner 2003, Emini & Koff 2004). Such a cellular response is advantageous because it can destroy infected cells unsusceptible to antibodies. The objective of many cell-mediated vaccines is to greatly enhance the pool of anti-HIV CD4+ memory cells and CD8+ CTLs in uninfected persons. The idea is that upon viral infection, the memory cells will proliferate rapidly and act to clear the infection (Emini & Koff 2004). The downside of this type of immunity is that it is highly specific and the high rate of HIV mutation results in the frequent escape of resistant HIV isolates from CTL-mediated elimination (Lehner 2003, Emini & Koff 2004). The susceptibility of the CTL response to viral escape has led to an effort to redirect vaccine studies to target the mucosal immune system and associated lymph nodes, enhance the rapid immune response, stimulate broad based adaptive immune responses, and utilize host antigens (Lehner 2003).
The mucosal associated lymphoid system has been well defined in the gastro-intestinal, respiratory and nasal tracts, at inductive sites of aggregated lymphoid tissue, such as Peyer’s patches in gut, and at effector sites in their respective mucosal tissues (Lehner 2003). Although a corresponding genital/rectal lymphoid system has not been defined, there is significant evidence that the iliac lymph nodes may function as an induction site from which the cells migrate to effector sites such as lamia propia and the rectum. Genital immunity in the mucosal associated lymphoid system has been demonstrated with oral and nasal immunization, with the purpose of inducing antibodies, which in turn elicit a local mucosal response, as well as a systemic T and B cell immune response. Mucosal immunization has been shown to successfully induce an immune response in the mucosa, regional lymph nodes, and the blood.
Currently, DNA vaccination is one of the hottest areas of HIV vaccine research. DNA vaccines contain DNA incorporated on a plasmid that encodes one or more protein antigens (web b). The DNA sequence incorporates a eukaryotic promoter to enable efficient transcription and translation within the transfected cell (Estcourt et al. 2004). Translated proteins are then cleaved into peptides, which are then exposed at the cell surface of class I histocompatibility molecules and serve to stimulate a protective immune response. A crucial requirement for a DNA vaccine is that the genetic information delivered should not integrate into the genome of the host. Chromosomal integration can cause deleterious effects, such as activation of oncogenes, inactivation of tumor-suppressor genes, and/ or chromosomal instability. DNA vaccines, after relatively short follow-up periods, have been invariably safe. DNA vaccines are delivered by injection into muscle and are often enhanced by the addition of genetic adjuvants that encode cytokines, chemokines, or costimulatory molecules.
There are a few DNA vaccines under clinical evaluation designed to help contend with diversity that have had encouraging preliminary results (Korber 2003). The vaccine VRC-HIVDNA009-00VP carries the gag, pol, and nef proteins from a clade B isolate, and an env protein from each of the clade isolates A, B, and C, and has been shown to induce CD4+ and CD8+ responses against the corresponding peptides. Several other polyvalent DNA vaccines directed against envelope protein variants from several different clades have also shown encouraging preliminary results in terms of antibody production.
In the last twenty years increased education and availability of drug therapy has helped to decrease rates of HIV transmission and slow the progression of AIDS in infected patients in affluent regions of the world such as the United States and Europe. Developing nations, however, have seen the rates of HIV transmission and the number persons dying from AIDS climb to alarming levels. Over 70% of HIV infections are in Africa, a continent which holds only 10% of the world’s population (Korber 2003). In sub-Saharan Africa, 7.5% of the adult population is infected, a number totaling 23.1 million, with an additional 1.9 million children living with HIV/AIDS (web d). AIDS has claimed the lives of 2.2 million and created 12.1 million orphans in sub-Saharan Africa alone (web d). The complexity of the world-wide AIDS pandemic continues to grow as statistics show HIV transmission rates increasing rapidly in the Caribbean and Southeast Asia (web c). The UNAIDS organization predicts that by the year 2010, 40 million children will be orphaned by AIDS and will grow up in a society where the age group usually responsible for providing economic and family stability is sick and dying (web c). The future of Africa presents enormous difficulties both socially and economically. An immense amount of foreign aid is required to help curb the AIDS epidemic through treatment, education, and the institution of social programs. Treatment regimens and monitoring methods must be made cheaper and simpler to facilitate treatment scale-ups urgently required in these resource poor areas. Further, although many African nations are willing to participate in vaccine trials, the health care infrastructure in these areas is far too primitive to meet the needs of such a venture.
In order for HIV research to have global significance, research and development should be conducted from a resource poor, community oriented perspective, with the potential to scale up dramatically to possibly meet the needs of millions of people (Goodwin 2004). Several global AIDS conferences convene each year to discuss the progress of vaccination trials, to ensure that money and resources for research are not wasted in duplication of effort, and for standardization of research (Goodwin 2004, Korber 2004). Current evidence from testing with synthetic vaccines show that the molecular approach is superior in inducing specific, strong and long lasting immunity while reducing the risks of unwanted side effects (Jiang & Koganty 2003). Fully synthetic vaccines have a long way to go in clinical development before they can be approved and available commercially (Jiang & Koganty 2003). New cost-efficient antiviral drugs with reduced side effects are currently needed by millions across the globe. With hard work and a few scientific breakthroughs there is hope for better and more effective therapies and vaccines against HIV in the future.
The statistics of HIV’s prevalence across the globe is mind-boggling. One positive idea to keep in mind is the notion that treatment supports prevention. Where treatment is available, the rates of transmission are likely to decrease as treated individuals have lower viral titers and are on average are less likely to transmit HIV (Goodwin 2004). In areas where antiretroviral therapies (ARV) are readily available, HIV incidence is reduced and the health of the public as a whole benefits. Further, stigma associated HIV testing generally decreases in areas with expanded ARV treatment and AIDS education, wherein people are on average more willing to know their status and to access prevention services (Goodwin 2004). Theoretically, the relationship between treatment technology and treatment should be mutually reinforcing; wherein large scale vaccine and microbicide trials in low/ middle income nations presents the opportunity to build a health care infrastructure, to create new jobs, and to improve/ expand treatment services (Goodwin 2004). Working towards successful preventative care worldwide is a complex and difficult venture. However, with proper organization, adequate funding, and an international investment there is potential to improve public health one region at a time.
Levy JA: HIV and the Pathogenesis of AIDS. Washington, DC: American Society of Microbiology, 1998.
Aderem A, Ulevitch RJ. 2000. Toll-like receptors in the induction of the innate immune response. Nature: 406(6797):782-7.
Boniotto M, Crovella S, Pirulli D, Scarlatti G, Spano A, Vatta L, Zezlina S, Tovo PA, Palomba E, Amoroso A. 2000. Polymorphisms in the MBL2 promoter correlated with risk of HIV-1 vertical transmission and AIDS progression. Genes Immun: 1(5):346-8.
Burton DR, Desrosiers RC, Doms RW, Koff WC, Kwong PD, Moore JP, Nabel GJ, Sodroski J, Wilson IA, Wyatt RT. 2004. HIV vaccine design and the neutralizing antibody problem. Nat Immunol: 5(3):233-6.
Bryant M & Ratner L. 1990. Myristoylation-dependent replication and assembly of human immunodeficiency virus 1. Proc Natl Acad Sci U S A: 87(2):523-7.
Cao YL, Qin L, Zhang J, Safritm Ho DD. 1995. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Eng J Med:322: 201-208.
Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. 1995. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science: 270(5243):1811-5.
Cormier EG and Dragic T. 2000. An overview of HIV-1 coreceptor function and its inhibitors. pp. 19-34 in HIV Sequence Compendium 2000. Edited by: Kuiken C, McCutchan F, Foley B, Mellors JW, Hahn B, Mullins J, Marx P, Wolinsky S, Korber B. Published by: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM.
Eigen M, Nieselt-Struwe K. 1990. How old is the immunodeficiency virus? AIDS: 4 Suppl 1:S85-93.
Emini EA, Koff WC. 2004. AIDS/HIV. Developing an AIDS vaccine: need, uncertainty, hope. Science: 304(5679):1913-4.
Estcourt MJ, McMichael AJ, Hanke T. 2004. DNA vaccines against human immunodeficiency virus type 1. Immunol Rev: 199:144-55.
De Vincenzu I, Ancell-Parks RA, Brunet JB, Costigliola P, Ricchi E, Chiodo F, Roumeliotou A, Papaevengelou G, Coutinhi RA, van Haastrecht HJA. 1992. Comparison of female to male and male to female transmission of HIV in 563 stable couples. Brit Med J:304:809-813.
Dunn DT, Newell ML, Ades AE, Peckham CS. 1992. Risk of human immunodeficiency virus type 1 transmission through breastfeeding. Lancet: 340(8819):585-8.
Feldman S, Stein D, Amrute S, Denny T, Garcia Z, Kloser P, Sun Y, Megjugorac N, Fitzgerald-Bocarsly P. 2001. Decreased interferon-alpha production in HIV-infected patients correlates with numerical and functional deficiencies in circulating type 2 dendritic cell precursors. Clin Immunol: 101(2):201-10.
Garred P, Madsen HO, Balslev U, Hofmann B, Pedersen C, Gerstoft J, Svejgaard A. 1997. Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin. Lancet: 349(9047):236-40.
Goedert JJ, Kessler CM, Aledort LM, Biggar RJ, Andes WA, White GC 2nd, Drummond JE, Vaidya K, Mann DL, Eyster ME, et al. 1989. A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med. 321(17):1141-8.
Goodwin J. 2004. HIV treatments, vaccines, and microbicides: toward coordinated advocacy. Canadian HIV/AIDS Policy & Law Review: 9(1):7-14.
Göttlinger HG. 2001. HIV-1 Gag: a Molecular Machine Driving Viral Particle Assembly and Release. pp. 2-28 in HIV Sequence Compendium 2001. Edited by: Kuiken C, Foley B, Hahn B, Marx P, McCutchan F, Mellors JW, Wolinsky S, Korber B. Published by: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, LA-UR 02-2877.
Hartshorn KL, Neumeyer D, Vogt MW, Schooley RT, Hirsch MS. 1987. Activity of interferons alpha, beta, and gamma against human immunodeficiency virus replication in vitro. AIDS Res Hum Retroviruses: 3(2):125-33.
Jiang ZH & Koganty RR. 2003. Synthetic vaccines: the role of adjuvants in immune targeting. Current Medicinal Chemistry: 10:1423-1439.
John GC, Nduati RW, Mbori-Ngacha D, Overbaugh J, Welch M, Richardson BA, Ndinya-Achola J, Bwayo J, Krieger J, Onyango F, Kreiss JK. 1997. Genital shedding of human immunodeficiency virus type 1 DNA during pregnancy: association with immunosuppression, abnormal cervical or vaginal discharge, and severe vitamin A deficiency. J Infect Dis: 175(1):57-62.
Karn J (2000). Tat, a novel regulator of HIV transcription and latency. 2000. pp. 2-18 in HIV Sequence Compendium. Edited by: Kuiken C, McCutchan F, Foley B, Mellors JW, Hahn B, Mullins J, Marx P, Wolinsky S. Published by: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM.
Korber Bette. 2003. AIDS Vaccine 2003: 18-21 September 2003, New York, NY, USA.. IDrugs 2003: 6(11):1046-1048.
Lackritz EM, Satten GA, Aberle-Grasse J, Dodd RY, Raimondi VP, Janssen RS, Lewis WF, Notari EP 4th, Petersen LR. 1995. Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. N Engl J Med: 28;333(26):1721-5.
Lecatsas G, Houff S, Macher A, Gelman E, Steis R, Reichert C, Masur H, Sever JL. 1985. Retrovirus-like particles in salivary glands, prostate and testes of AIDS patients. Proc Soc Exp Biol Med: 178(4):653-5.
Levy JA, Scott I, Mackewicz C. 2003. Protection from HIV/AIDS: the importance of innate immunity. Clin Immunol: 108(3):167-74.
Lehner T, Wang Y, Cranage M, Bergmeier LA, Mitchell E, Tao L, Hall G, Dennis M, Cook N, Brookes R, Klavinskis L, Jones I, Doyle C, Ward R. 1996. Protective mucosal immunity elicited by targeted iliac lymph node immunization with a subunit SIV envelope and core vaccine in macaques. Nat Med: 2(7):767-75.
Lehner T, Wang Y, Cranage M, Tao L, Mitchell E, Bravery C, Doyle C, Pratt K, Hall G, Dennis M, Villinger L, Bergmeier L. 2000. Up-regulation of beta-chemokines and down-modulation of CCR5 co-receptors inhibit simian immunodeficiency virus transmission in non-human primates. Immunology: 99(4):569-77.
Lehner T. 2003. Innate and adaptive mucosal immunity in protection against HIV infection. Vaccine: 21 Suppl 2:S68-76.
Marlink R. 1996. Lessons from the second AIDS virus, HIV-2. AIDS. Jun;10(7):689-99.
Moore JP, Parren PW, Burton DR. 2001. Genetic subtypes, humoral immunity, and human immunodeficiency virus type 1 vaccine development. J Virol: 75(13):5721-9.
Myers G. Tenth anniversary perspectives on AIDS. HIV: between past and future. AIDS Res Hum Retroviruses. 1994 Nov;10(11):1317-24.
Nahmias AJ, Weiss J, Yao X, Lee F, Kodsi R, Schanfield M, Matthews T, Bolognesi D, Durack D, Motulsky A, et al. 1986. Evidence for human infection with an HTLV III/LAV-like virus in Central Africa, 1959. Lancet. May 31;1(8492):1279-80.
Nduati RW, John GC, Richardson BA, Overbaugh J, Welch M, Ndinya-Achola J, Moses S, Holmes K, Onyango F, Kreiss JK. 1995. Human immunodeficiency virus type 1-infected cells in breast milk: association with immunosuppression and vitamin A deficiency. J Infect Dis: 172(6):1461-8.
Nielsen K, Boyer P, Dillon M, Wafer D, Wei LS, Garratty E, Dickover RE, Bryson YJ. 1996. Presence of human immunodeficiency virus (HIV) type 1 and HIV-1-specific antibodies in cervicovaginal secretions of infected mothers and in the gastric aspirates of their infants. J Infect Dis: 173(4):1001-4.
Nuovo GJ, Forde A, MacConnell P, Fahrenwald R. 1993. In situ detection of PCR-amplified HIV-1 nucleic acids and tumor necrosis factor cDNA in cervical tissues. Am J Pathol: 143(1):40-8.
Piguet V and Trono D (1999). A Structure-function analysis of the Nef Protein of Primate Lentiviruses. pp. 448-459 in Human Retroviruses and AIDS 1999. Edited by: Kuiken CL, Foley B, Hahn B, Korber B, McCutchan F, Marx PA, Mellors JW, Mullins JI, Sodroski J, and Wolinksy S. Published by: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM.
Ruff AJ, Coberly J, Halsey NA, Boulos R, Desormeaux J, Burnley A, Joseph DJ, McBrien M, Quinn T, Losikoff P, et al. 1994. Prevalence of HIV-1 DNA and p24 antigen in breast milk and correlation with maternal factors. J Acquir Immune Defic Syndr: 7(1):68-73.
Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. 1996. The risk of transfusion-transmitted viral infections. The Retrovirus Epidemiology Donor Study. N Engl J Med. 334(26):1685-90.
Soumelis V, Scott I, Gheyas F, Bouhour D, Cozon G, Cotte L, Huang L, Levy JA, Liu YJ. 2001. Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients. Blood: 98(4):906-12.
Soumelis V, Scott I, Liu YJ, Levy J. 2002. Natural type 1 interferon producing cells in HIV infection. Hum Immunol: 63(12):1206-12.
UNAIDS. AIDS epidemic Update: December, 2001. 2001, UNAIDS/WHO : Geneva.
Vernazza PL, Eron JJ, Cohen MS, van der Horst CM, Troiani L, Fiscus SA. 1994. Detection and biologic characterization of infectious HIV-1 in semen of seropositive men. AIDS: 8(9):1325-9.
Wagner L, Yang OO, Garcia-Zepeda EA, Ge Y, Kalams SA, Walker BD, Pasternack MS, Luster AD. 1998. Beta-chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. Nature: 391(6670):908-11.
Yamamoto JK, Barre-Sinoussi F, Bolton V, Pedersen NC, Gardner MB. 1986. Human alpha- and beta-interferon but not gamma- suppress the in vitro replication of LAV, HTLV-III, and ARV-2. J Interferon Res: 6(2):143-52.
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
- best immunity boosting tea
- tea for immunity boost
- immunity boosting tea
- covid immunity news
- immunity to covid after infection
- frontiers cellular and infection microbiology
- wbc and infection vs inflammation
- immunity vs inflammation
- immunity and infection
- covid immunity updates
- how long does immunity after covid last
- infection and immunity impact factor