Retroviral diseases are typically characterized by restricted viral gene expression, latency, and lifelong persistence of virus in the face of substantial host immune responses. From cohort studies of individuals infected with HIV-1 at known points in time, it is estimated that between 26 and 36% of infected individuals develop AIDS within 7 years of infection and that an additional 40% develop lesser signs of immune dysfunction. This protracted clinical course suggests that expression of the HIV-1 genome in vivo is downregulated as compared to in vitro infection of lymphocytes by HIV-1, which is characterized by explosive lytic viral infection.

Initial infection with HIV-1 frequently causes an acute viral syndrome with protean manifestations most frequently characterized by fever, lymphadenopathy, pharyngitis, and rash. Other symptoms and signs that may occur with acute HIV-1 infection include myalgias and arthalgias, leukopenia, thrombocytopenia, nausea, diarrhea, headache, and encephalopathy.

During this primary phase of infection, symptoms are accompanied by highlevel HIV-1 plasma viremia, with peak titers reaching 107 virions per milliliter. Viremia is also accompanied by high levels of circulating HIV-1 p24 antigen, only part of which is virion-associated, the remainder circulating alone or complexed with immunoglobulin. Studies of individuals who have become infected with HIV-1 at defined points in time have shown that there is a relatively prolonged “window” period ranging from 2 weeks to 6 months during which patients remain antibody-negative. During this time, they may or may not have symptoms of acute infection prompting medical attention. Generally, such patients become p24 antigenemic in the few days or weeks immediately preceding seroconversion. Subsequently, antibodies to viral core and envelope proteins appear coincident with resolution of clinical symptoms. An important recent finding regarding HIV-1 pathogenesis is that viral replication is only partially controlled in the months and years following infection and seroconversion. That is, the initial high levels of virus produced in lymphoid tissues and circulating in plasma in titers of 10⁶ to 10⁷ virions per milliliter decrease only to levels of 10³ to 10⁵ virions per milliliter. This indicates that even during the clinically quiescent stages of infection substantial viral replication ensues, leading to progressive CD4 cell destruction. This serves as the rationale for clinical studies examining the utility of antiviral therapy earlier in the disease process.

The protracted clinical course of HIV-1 infection raises clinically relevant questions regarding viral pathogenesis: What are the mechanisms responsible for CD4+ cell loss in vivo? What are the viral and host interactions that underlie the chronicity of HIV-1 infection? The precise biologic mechanisms responsible for the cytopathic effects of HIV-1 in vivo are not known. Molecularly cloned HIV-1 proviral DNA, transfected into human cells, has been shown in cell culture experiments to contain all necessary information to generate infectious and cytopathic virus. Thus, there is no question that HIV-1 alone has the potential for direct cytopathic activity against CD4+ lymphocytes in vitro and in vivo. Expression of only the HIV-1 envelope on lymphocytes is sufficient for inducing fusion of cells with normal uninfected CD4+ bystander cells, suggesting that syncytium formation mediated by gp120-CD4 interaction may also contribute to cell loss in vivo. However, other mechanisms of CD4 cell loss may also be operative. Cell-free HIV-1 gp120 envelope protein has been shown to adsorb to CD4+ cells and could serve as an effective antigen for mediating antibody-dependent cell-mediated cytotoxicity, and when processed by antigen-presenting cells, to constitute a target for direct T-cell cytotoxicity. The relative importance of these processes to CD4 cell loss in vivo remains to be determined. Similarly, in the CNS of infected individuals, wherein the predominant cell types infected with HIV-1 are cells of the monocyte/macrophage lineage, additional mechanisms of cytopathology are likely involved. Possibilities include the elaboration of cytotoxic factors from infected cells and interference with neurotropic factors both leading to the clinically recognized AIDS dementia complex.

Viral and host factors responsible for the partial downregulation of HIV-1 replication following initial infection are also largely unknown. A strong humoral and cellular immune response to HIV-1 has been documented on the basis of ELISA, immunoblot, and radioimmunoprecipitation assays of patient sera and cell-mediated cytotoxicity to target cells displaying viral antigens. Neutralizing antibodies, antibody-dependent cell-mediated cytotoxicity, antibody-dependent complement-mediated cytotoxicity, MHC-restricted virus-specific cytotoxic T-lymphocyte-mediated cytotoxicity, and NK cell-mediated cytotoxicity have all been found to have activity against HIV-1 in vitro and may play an important role in the downmodulation of viral replication. However, the relative efficacy of the various immune effector arms and the changes that occur with time which eventually allow uncontrolled viral replication are unknown.

An additional component of the viral-host interaction of potentially great clinical importance is the regeneration capacity of the immune system. Recent studies of the clinical effects of novel, potent inhibitors of HIV-1 reverse transcriptase and protease genes indicate that patients with even severely depressed CD4 lymphocyte counts can experience substantial increases in such cells. Such responses have been of limited duration, however, owing to the development of viral resistance to these drugs. Yet they illustrate the potential benefits that may accrue if more effective antivirals are developed.

Genetic variability is a hallmark of HIV-1. The variability of the HIV-1 genome is characteristic of retroviruses in general because reverse transcription of viral RNA into proviral DNA and transcription of proviral DNA into genomic viral RNA are not subject to cellular proofreading mechanisms. The rate of nucleotide misincorporation by the viral reverse transcriptase is of the order of 10^-4 per nucleotide per replication cycle. Because the HIV-1 genome is 10⁴ nucleotides in length, this high rate of nucleotide misincorporation means that virtually no two viruses are identical and that HIV-1 isolates must, by definition, be described in terms of a “quasispecies” composed of populations highly related by distinct viral genomes. Direct nucleotide sequence analysis of uncultured, virally infected human tissues using polymerase chain reaction amplification has confirmed these findings. The clinical importance of HIV-1 variability is still not fully understood. However, it is clear that viral resistance to reverse transcription inhibitors and protease inhibitors commonly develops and limits the effectiveness of these agents. Antigenic properties of the virus may also vary, thereby limiting the effectiveness of the immune response. Moreover, genetic variability leads to biologic changes in the virus over time, frequently resulting in the accumulation of virus strains with pronounced syncytium-including (SI) phenotypes in late stages of infection. Such a switch from non-SI to SI virus strains in vivo carries a worsened clinical prognosis.