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Adv Dent Res 19:10-16, April, 2006
© 2006 International and American Associations for Dental Research

HIV Pathogenesis: Knowledge Gained after Two Decades of Research

Presented at the Fifth World Workshop on Oral Health and Disease in AIDS, Phuket, Thailand, July 6–9, 2004, sponsored by Prince of Songkla University, Thailand, the International Association for Dental Research, the World Health Organization, the NIDCR/National Institutes of Health, USA, and the University of California-San Francisco Oral AIDS Center.

J.A. Levy

Director, Laboratory for Tumor and AIDS Research, University of California, San Francisco, 513 Parnassus Avenue, Suite S1280, San Francisco, CA 94143-1270, USA; jalevy{at}itsa.ucsf.edu


   Abstract
TOP
 Abstract
Introduction
 Discovery of HIV
 Host Immune Responses to...
 CD4+ Cell Loss
 Antiviral Therapy
 Future Directions
 Constantly Changing Concepts
 References
 
Great progress has been made in our understanding of HIV since its initial discovery about 20 years ago. The ability of HIV to infect CD4+ lymphocytes and a wide variety of other cells in the body is appreciated, as is its role in immunologic, gastrointestinal, and brain disorders. HIV enters cells via the CD4 molecule, chemokine co-receptors (CXCR4, CCR5), and other cell-surface proteins. Several accessory virus-associated genes (e.g., Rev, Tat, Nef) have uncovered unique pathways that can also be observed in normal cells. Recently, the discovery of natural cellular resistant factors (APOBEC3G and TRIM5a) has provided avenues for novel antiviral therapies. Studies of long-term survivors have given insight into immune responses that control HIV and can prevent infection. Neutralizing antibodies and CD8+ cell cytotoxic responses, as well as plasmacytoid dendritic cells and CD8+ cell non-cytotoxic antiviral responses, are adaptive and innate immune activities mediating this anti-HIV effect. HIV vaccine studies have indicated that conventional approaches do not work against this integrated intracellular parasite. While much has been learned about HIV, more details are needed about its infection cycle and its pathologic effects in the body. The past 20 years have yielded important information on HIV/AIDS that should lead to effective anti-HIV therapies and a vaccine.

KEY WORDS: HIV • pathogensis • immune response • CD4+ cells • therapy


   Introduction
TOP
 Abstract
 Introduction
Discovery of HIV
 Host Immune Responses to...
 CD4+ Cell Loss
 Antiviral Therapy
 Future Directions
 Constantly Changing Concepts
 References
 
When the acquired immune deficiency syndrome (AIDS) first appeared in San Francisco, it was initially described in homosexual men and was called the ‘gay-related immune deficiency syndrome’ (GRID). In 1981, it was more appropriately re-named AIDS, and the San Francisco Chronicle newspaper published a description of the ‘seven deadly symptoms’ associated with the disease: a fever persisting for more than 4 or 5 days; unexplained weight loss of 10 to 20 pounds in a few months; general aches and pains similar to an acute viral syndrome for more than 10 days; sore or swollen lymph glands for more than a week; appearance of blue or purplish spots on the skin (now recognized as Kaposi’s sarcoma); herpes sores that worsen and persist for more than 5 weeks; and loss of sensory or motor ability or defects in mental or neurological function. These clinical features remain today as characteristics of HIV infection.

The confusion that emerged in San Francisco about the cause of AIDS evolved around whether it was a new agent or a variant of a previously known one (e.g., hepatitis B virus, cytomegalovirus, or Epstein-Barr virus). Alternatively, some considered the possibility that AIDS was caused not by an infectious agent but by an overdose of drugs or stress to the immune system. For infectious disease clinicians, the challenge was to identify the causative microbial agent.


   Discovery of HIV
TOP
 Abstract
 Introduction
 Discovery of HIV
Host Immune Responses to...
 CD4+ Cell Loss
 Antiviral Therapy
 Future Directions
 Constantly Changing Concepts
 References
 
Within 2 years after AIDS was defined, a virus was recovered from a person with the lymphadenopathy syndrome which many considered a pre-condition of AIDS. The virus, isolated by Françoise Barré-Sinoussi et al.(1983), had the unusual characteristic of infecting peripheral blood mononuclear cells (PBMC) and causing cytopathic effects within 6 or 7 days. Examined by electron microscopy, it had the morphology of a budding retrovirus, later recognized as a lentivirus (Gonda et al., 1985). This virus was unlike the human T-cell leukemia virus (HTLV), a previously described human retrovirus that can cause leukemia (Poiesz et al., 1980). This lymphadenopathy-associated virus (LAV) did not establish a transformed state in CD4+ cells, but caused cell death after high-level replication (Barré-Sinoussi et al., 1983).

After this description of LAV by Luc Montagnier’s laboratory (Barré-Sinoussi et al., 1983), two other groups reported the isolation of retroviruses from AIDS patients. The first described a virus which they called HTLV III, because they believed it to be part of the HTLV family of oncogenic retroviruses (Gallo et al., 1984), and the second, working with subjects from San Francisco, noted the presence of retroviruses with characteristics of cytopathic agents such as LAV (Levy et al., 1984) (Fig. 1Go). Thus, it was concluded that they could not be transforming viruses like HTLV and were called AIDS-associated retroviruses (ARV) (Levy et al., 1984). With time, the retroviruses isolated by all three research groups were found to have similar features, although being somewhat distinct—a characteristic now further appreciated through other research findings (Levy, 1998). These viruses were renamed the human immunodeficiency virus (HIV) (Coffin et al., 1986). Shortly after the identification of HIV, another human retrovirus was recovered from West African patients with AIDS (Clavel et al., 1986). It was noted to be sufficiently different genetically from HIV-1 (by up to 40%) and was named HIV-2.


Figure 1
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  		Fig. 1 - Cytopathic changes induced in peripheral blood mononuclear cells by ARV-2, an early HIV-1 isolate.

 
Cloning and sequencing of HIV
After the isolation of ARV, its molecular cloning was accomplished (Luciw et al., 1984), followed by sequencing of the ARV-2 isolate (Sanchez-Pescador et al., 1985). HIV was then found by several groups to consist of 9 separate genes coding for 3 structural (Gag, polymerase, Env) and 6 accessory proteins (Vif, Vpr, Vpu, Rev, Tat, Nef). Similar to other retroviruses, HIV had a long-terminal repeat (LTR), which served as the promoter region for transcription of the virus. The overall structure of the virion with its various components was defined, and the envelope gp120 and gp41 were found in knobs projecting from the outside lipid coat. The inner core, a p24 Gag protein, was described along with the Gag matrix protein (MA) that helps to maintain the structure of the virion (Levy, 1998).

The HIV accessory proteins have been very helpful in revealing functions of not only HIV-1 proteins, but also biologic activities associated with normal cellular proteins (Table 1Go). These accessory proteins define the complex nature of this lentivirus and offer an understanding of how HIV has evolved ways to infect a variety of different cell types, to mutate (because of the high error rate of its reverse transcriptase), and to maintain itself within the infected host through virus integration and latency (Levy, 1998).


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  		TABLE 1 - HIV Accessory Proteins and Their Functions
 
Detection assays for HIV
With the recognition of AIDS, various assays for detection of HIV needed to be developed (Table 2Go). Reverse transcriptase was used for determining the virus’ presence in cell culture (Hoffman et al., 1985), and immunofluorescence assays (Kaminsky et al., 1985), ELISAs, and the Western blot helped detect antibodies to HIV (Levy et al., 1984; Levy, 1998). These tests all formed the basis for confirmatory assays for HIV infection. Subsequently, based on the polymerase chain-reaction (PCR), viral RNA levels in the blood could be determined and measured through RT-PCR procedures (Piatak et al., 1993). This approach has been particularly useful in monitoring the effect of antiviral treatment in HIV-infected individuals (see below).


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  		TABLE 2 - Assays for Detection of HIV Infection
 
The effect of HIV on the immune system was greatly helped by the development of flow cytometry in the 1970s (Cantor et al., 1975). This technology enabled clinical and research laboratories, via selective monoclonal antibodies, to determine the number of CD4+ and CD8+ cells in people. While the CD4+/CD8+ cell ratio is usually 2:1, it was very soon recognized that the ratio in infected individuals often was reduced to less than 1 (Gottlieb et al., 1981; Mildvan et al., 1982). The number of CD4+ cells, usually in the range of 600 to 1200 cells/µL, became reduced over time, particularly in progressors, to the low hundreds (e.g., < 300 cells/µL). These findings supported the observation that the CD4+ lymphocyte was a major target for HIV replication and cell death (Klatzmann et al., 1984a). Shortly thereafter, the receptor on CD4+ cells was found to be the major attachment site for the virion (Klatzmann et al., 1984b).

HIV heterogeneity
Despite the great progress made in understanding HIV/AIDS in the early 1980s, some observations challenged certain findings at the time: All CD4+ cells were not susceptible to the virus, and CD4-negative cells could be infected by HIV. These findings led groups to recognize that galactosylceramide (Gal-C) could be another receptor for HIV, particularly in brain and bowel cells (Harouse et al., 1989; Fantini et al., 1993). Importantly, the virus itself was noted to have two major differences in its replicative ability in host cells. While all HIV isolates grew well in most primary CD4+ cells, some isolates grew very well in primary macrophages, whereas others productively infected established CD4+ T-cell lines (Cheng-Mayer et al., 1988a). These cellular host range differences defined two biologic phenotypes. The macrophage-tropic viruses were found not to induce multi-nucleated syncytia in T-cell lines (e.g., MT-2), whereas the T-cell-line tropic viruses did. They subsequently became known biologically as non-syncytia-inducing (NSI) and syncytia-inducing (SI) viruses (Fenyo et al., 1988; Tersmette et al., 1988).

The reason for these host range differences was appreciated much later, when it was recognized that these viruses used different chemokine co-receptors for entry into target cells (Berger et al., 1999). After attachment to CD4 on CD4+ cells, further binding occurred via the viral envelope V3 loop to a chemokine co-receptor, and then entry took place. The NSI virus used the CCR5 chemokine receptor (R5 isolates), whereas the SI virus used the CXCR4 receptor (X4 isolates). The processes leading to viral entry are still not fully defined. For example, after virus attachment, fusion takes place but the fusion receptor on the cell has not been defined. We also do not know how the viral capsid enters the cells. Conceivably, separate biologic events are involved in these events (Levy, 1996).

HIV transmission and cellular host range
An important consideration in understanding HIV transmission was the role of the virus-infected cell in transmitting HIV not only to immune cells but also to macrophages and mucosal-lining cells (Levy, 1988). These infected cells (lymphocytes and macrophages) are found in genital fluids (Fig. 2Go). Several electron microscopy studies have shown that, whereas HIV alone may not directly infect cultured cervical-lining cells or mucosal cells from the bowel, infected T-cells and macrophages can efficiently deliver virus to these infected cells (Phillips, 1994). Time-lapse photography has shown that the infected cells, remaining viable, can move from one mucosal-lining cell to the other, delivering virus, and thus emphasizing this important means of transmission. Infection of the bowel mucosae through HIV-infected cells in genital fluid could account for the infected cells noted in mucosal-lining cells of the bowel (Fig. 3Go) as well as the cervix (Nelson et al., 1988; Levy, 1998).


Figure 2
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  		Fig. 2 - Virus-infected cells in seminal fluid as detected by in situ hybridization. From Levy (1988); reprinted with permission.

 

Figure 3
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  		Fig. 3 - Virus-infected cells detected by in situ hybridization in mucosal lining cells of the bowel. From Nelson et al.(1988); reprinted with permission.

 
Other work in this field during the late 1980s and early 1990s indicated the wide cellular host range of HIV, infecting several cell types of the brain, as well as the bowel, heart, kidney, liver, testes, prostate, and other organs (Table 3Go) (Levy, 1998). Virus replication in the lymphoid tissues mirrors the progression of HIV infection in individuals—destruction of the germinal centers in the lymph node, accompanied by increased virus expression in the lymphoid tissues (Pantaleo et al., 1993).


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  		TABLE 3 - Human Cells Susceptible to HIV
 
HIV replication and latency
Observations in many laboratories defined the nature of the HIV replicative cycle, which involved reverse transcription, integration, and proteolytic activities of the three enzymes encoded by the virus. The HIV reverse transcriptase, integrase, and protease have become targets for antiviral therapies. With these observations in HIV replication came the recognition that this retrovirus, as had been seen with other retroviruses, can infect and replicate to very low levels or remain latent (Table 4Go). The mechanism for this latency, or ‘silent virus’ state, has not been elucidated but could be related to DNA methylation or direct activity of the host cellular products on the integrated HIV genome (Levy, 1998).


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  		TABLE 4 - Retrovirus Latency and Persistence
 
These differences in virus replication also indicated that an HIV isolated early in the infection, when the infected individual was asymptomatic, replicated more slowly and to a lower level than the virus recovered later, when the individual progressed to disease (Asjo et al., 1986; Cheng-Mayer et al., 1988a) (Fig. 4Go). These biologic features emphasized what we now recognize as a change from the R5 NSI type virus to an X4 SI virus, which is associated with increased destruction of CD4+ lymphocyes. Essentially, the replicative cycle, which can lead to the emergence of up to 10 mutations per replication cycle, can give rise to highly cytopathic strains and viruses that can infect other tissues, such as the brain, the bowel, and the kidney (Levy, 1998).


Figure 4
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  		Fig. 4 - Differences in replication of HIV-1 recovered from an individual early in infection ({circ}) and later, when he had progressed to disease ({triangleup}) (Cheng-Mayer et al., 1988b). Note that the early virus replicates at low titer, and peaks after a longer period of time than the faster-replicating virus, recovered later at the time of disease.

 

   Host Immune Responses to HIV
TOP
 Abstract
 Introduction
 Discovery of HIV
 Host Immune Responses to...
CD4+ Cell Loss
 Antiviral Therapy
 Future Directions
 Constantly Changing Concepts
 References
 
What can the infected individual do to control this HIV infection? Now that viral RNA levels in the blood can be measured by PCR techniques, the observation was made that, within 8 to 12 weeks after infection, HIV reaches levels as high as several million RNA molecules/mL, and then is reduced to much lower levels (5000 to 15,000 molecules/mL), or even to an undetectable level. The lower the viral set point, the better the long-term prognosis for the infected person (Mellors et al., 1996). These observations led to the suggestion that some immune responses were controlling the infection, at least for this period of time.

Anti-HIV neutralizing antibodies
One of the first anti-HIV immunologic responses recognized was the presence of neutralizing antibodies that, initially, seemed to be able to inactivate several HIV strains (Robert-Guroff et al., 1985; Javaherian et al., 1990). Based on serum from three different individuals, our laboratory suggested a potential classification of HIV according to their sensitivity to neutralization by three different sera (Cheng-Mayer et al., 1988b): Some viruses were very sensitive (A), some moderately sensitive (B), and some completely resistant to neutralization (D) (e.g., SF170) (Table 5Go). Subsequent work has shown that this virus neutralization is rarely broad enough to handle the variety of different envelope antigens present in different virus isolates. That challenge faces us with vaccine development.


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  		TABLE 5 - Neutralization Subtypes of HIV
 
During the evaluation of virus neutralization, Jacques Homsy, in my group, noted that antibodies from some sera enhanced virus replication through interaction with the Fc receptor (Homsy et al., 1989). Essentially, when followed over time, healthy individuals showed antibody neutralization of the virus strain obtained at the time of the serum sample. As that person advanced to disease, however, the serum obtained from that individual enhanced, by up to 300%, the HIV recovered at that same time (Homsy et al., 1990). This antibody-mediated enhancement thus appeared to be a detrimental effect of the humoral response. Similar observations have been made with complement-mediated antibody enhancement of HIV infection (Robinson et al., 1990).

Other harmful effects of antibodies, not currently given enough attention, are auto-antibodies circulating in the blood of individuals with HIV infection (Table 6Go). These auto-antibodies can lead to several clinical conditions involving the loss of certain peripheral blood cells (e.g., neutropenia, thrombopenia) and to neuropathies (Levy, 1998).


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  		TABLE 6 - Autoantibodies Detected in HIV Infection
 
Cellular immunity
As an infected individual advanced to disease, the predominant immune response went from type 1 (cell-mediated immunity) to type 2 (antibody production) (Clerici and Shearer, 1993). While these observations have not been noted consistently in all studies, they form a framework by which clinicians and researchers can begin to evaluate whether the presence of a type-1- or type-2-dominant response is found in healthy individuals compared with those advancing to disease. It would appear that a type-1 response (i.e., cellular immunity) is most beneficial in HIV infection.

In studies of clinically healthy infected men in the early 1980s, a new mechanism for CD8+ cell control of HIV infection was discovered: suppression of virus replication without killing the infected cell (Walker et al., 1986). This CD8+ cell non-cytotoxic antiviral response (CNAR) was the first cellular immune response against HIV described, and it was associated with a clinically healthy state. CNAR appears to be mediated by a novel soluble protein, the CD8+ cell anti-HIV factor (CAF) (Walker and Levy, 1989), that has not yet been identified. Subsequently, classic adaptive cytotoxic T-cell anti-HIV responses were noted in infected individuals (Plata et al., 1987). Thus, in HIV infection, two functions of the CD8+ cell antiviral response can be found: the conventional cytotoxic response and a novel non-cytotoxic suppression that had not previously been recognized in any microbial infections.


   CD4+ Cell Loss
TOP
 Abstract
 Introduction
 Discovery of HIV
 Host Immune Responses to...
 CD4+ Cell Loss
Antiviral Therapy
 Future Directions
 Constantly Changing Concepts
 References
 
The mechanism for CD4+ cell loss still is not explained. Various reasons have been presented (Table 7Go). The most likely cause for the greatest reduction in these cells is activation-induced cell death by apoptosis (Ameisen, 1992). This programmed cell death occurs following HIV infection of macrophages or CD4+ cells, with the production of various cytokines that can induce this normal mechanism for cell death.


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  		TABLE 7 - Mechanisms for CD4+ Cell Loss
 
Long-term survivors
Long-term survivors (LTS), who have been infected for 10 years or more with normal CD4+ cell counts and are clinically healthy without treatment, have certain characteristics reflecting a beneficial anti-HIV immune response (Table 8Go): the presence of neutralizing antibodies and a lack of enhancing antibodies; the presence of anti-HIV CTL and certain innate immune responses, such as CNAR; and high levels of interferon-producing cells or plasmacytoid dendritic cells (PDC) (Levy, 1993; Levy et al., 1996; Soumelis et al., 2001). These latter innate responses, not previously given much attention in HIV infection, can influence the disease course (Levy, 2001). Obviously, the host immune response is a major determinant in the course of HIV infection.


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  		TABLE 8 - Characteristics of Long-term Survivors
 

   Antiviral Therapy
TOP
 Abstract
 Introduction
 Discovery of HIV
 Host Immune Responses to...
 CD4+ Cell Loss
 Antiviral Therapy
Future Directions
 Constantly Changing Concepts
 References
 
The fact that we can measure HIV RNA levels in the blood permits us to evaluate treatments that could directly attack the virus and reduce its ability to replicate in the host. These viral dynamics were used to examine, initially, monotherapy and, later, combined therapy, now known as highly active anti-retroviral therapy (HAART), which is generally given as a three-drug combination. Over 20 anti-HIV drugs are now available for treatment (Fauci, 2003).

Some novel therapies under consideration include the use of RNA interference, which targets specific viral genes (Lieberman et al., 2003), and drugs that block virus interaction with the chemokine co-receptors (Trkola et al., 2002) or fusion at entry into cells (e.g., Fuzeon) (Cammack, 2001).

Natural cellular resistance
A major potentially beneficial observation made over the last two years is the presence within cells of natural mechanisms for limiting HIV replication (Table 9Go). These findings offer novel approaches to anti-HIV therapies. These cell resistances are recognized because they are sometimes countered by HIV proteins. For example, APOBEC-3G, a cytosine deaminase that creates mutations in the HIV genome at the DNA template level, is countered by the Vif protein, which prevents the APOBEC-3G protein from functioning in the infected cell (Sheehy et al., 2002; Mangeat et al., 2003). Restriction of HIV in monkey cells has been shown to be related to the presence of a cellular protein, TRIM5{alpha}, that appears to limit the opening of the HIV capsid within the cell (Stremlau et al., 2004). A gene product Murr-1 inhibits degradation of I{kappa}B{alpha} and therefore can play a role in creating and/or maintaining latency within the cell (Ganesh et al., 2003). Finally, still to be identified is a human cellular restriction factor for HIV particle production that is counteracted by Vpu (Varthakavi et al., 2003).


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  		TABLE 9 - Natural Cellular Resistance to HIV Replication
 

   Future Directions
TOP
 Abstract
 Introduction
 Discovery of HIV
 Host Immune Responses to...
 CD4+ Cell Loss
 Antiviral Therapy
 Future Directions
Constantly Changing Concepts
 References
 
While HAART has, for many years, facilitated the control of HIV infection in individuals who are suffering from disease and even AIDS, the long-term control of this virus will require new directions (Table 10Go). Besides consideration of latent infections, the emergence of recombinant viruses may challenge therapies, if strains resistant to immune responses or HAART evolve (Thomson et al., 2002). The virus-infected cell remains a mechanism for HIV transfer, since anti-retroviral drugs do not directly eliminate this source of the virus.


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  		TABLE 10 - Future Directions
 
Further work should be done toward boosting the immune response via both the adaptive and the innate immune systems and, of course, the development of an effective vaccine. Innate immune responses are particularly important at mucosal sites of HIV transmission (Levy, 2001). One emphasis for future therapies is to restore the immune system to that of long-term survivors who can control HIV infection. This approach would include a variety of cytokines, including IL-2, IL-15, IFN-alpha, IL-7, and, when fully identified, CAF. In vaccine development, these same cytokines can act as beneficial adjuvants along with CpG (Dumais et al., 2002), G-CSF, and Flt-3 (Pulendran et al., 2000) that help elicit innate immune responses.


   Constantly Changing Concepts
TOP
 Abstract
 Introduction
 Discovery of HIV
 Host Immune Responses to...
 CD4+ Cell Loss
 Antiviral Therapy
 Future Directions
 Constantly Changing Concepts
References
 
In the past 20 years, the identification of AIDS and the characterization of its causative agent, HIV, have been progressing at a very rapid rate. According to many experts, this virus is the best-understood agent that causes human disease. Importantly, what we have learned over these two decades is that concepts that were initially considered conclusive were subsequently shown to be incorrect (Table 11Go).


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  		TABLE 11 - Constantly Changing Concepts
 
New discoveries have provided novel avenues for improvement in prevention, vaccine development, and care. Above all, we need to emphasize the approaches that target not only the causative agent, HIV, but also the host immune response. In this regard, with sufficient attention to this objective by researchers in public and private institutions, we should be able to see immune control of HIV to the state achieved by long-term survivors.


   References
TOP
 Abstract
 Introduction
 Discovery of HIV
 Host Immune Responses to...
 CD4+ Cell Loss
 Antiviral Therapy
 Future Directions
 Constantly Changing Concepts
 References
 
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