The initial phase of HIV-1 infection is characterized by high-level viremia, associated with the ability to detect the viral core protein p24 in the serum. However, soon after infection the level of viremia and p24 antigenemia rapidly decrease (see Fig. 407-6). A long period of relatively asymptomatic infection ensues, suggesting that virus-specific immune responses may play a role in limiting viral replication and thereby disease progression. With the AIDS epidemic now entering its third decade, identification of the precise protective components of anti-HIV immunity remains an elusive goal, although significant progress has been made.

Neutralizing Antibodies
HIV infection induces B lymphocytes to produce antibodies directed against viral proteins, and some of these antibodies are capable of neutralizing the virus. Antibody responses are typically observed 1 to 3 months after primary infection, although longer periods before antibody responses develop have been documented in rare instances. Neutralizing antibodies directly neutralize free virus at a stage before the virus has entered the cell and become uncoated. In a number of viral infections, neutralizing antibody induced by immunization correlates with protection from subsequent viral infection. HIV-1 infection results in the production of HIV-specific antibodies directed at a number of viral proteins, and some of these antibodies demonstrate neutralizing activity. The primary target of neutralizing antibodies is the envelope glycoprotein, in particular a loop structure within a relatively hypervariable region of the gp120 glycoprotein termed the principal neutralizing domain or V3 loop, as well as epitopes in the region involved in CD4 binding that recognize conformationally determined regions that are composed of discontinuous segments brought together in the tertiary structure of the envelope protein.

Neutralizing antibodies have been demonstrated to be present at all stages of HIV-1 infection, and although titers are generally lower in later stages of illness, attempts to correlate neutralizing antibody titers with disease progression have yielded conflicting results. Detailed studies in primary HIV-1 infection have demonstrated that antibodies capable of neutralizing the infecting strain of virus appear after clearance of the primary viremia, suggesting that other immune mechanisms may be important in the early control of viremia. In addition, it has been demonstrated that antibodies from infected persons at a given point in time tend to be poorly able to neutralize the infecting strain of virus, but much better at neutralizing laboratory strains of virus. Although a number of animal studies have shown that neutralizing antibodies can confer protection against viral challenge, this protection has been largely in highly idealized situations in which maximal titers were induced just prior to challenge and a low inoculum of virus was given intravenously. Whether induction of neutralizing antibodies alone would be able to confer protection against naturally acquired infection is not known, but it will be important for vaccine candidates to be able to induce these responses.
The ability of HIV-specific neutralizing antibodies to confer protection may be impaired in part by the high degree of antigenic variation exhibited by HIV. This antigenic variation is particularly pronounced in the envelope region of the virus, and virus variants may emerge within an infected individual that are neutralization resistant.

This also has significant implications for vaccine design, because neutralizing antibodies generated in response to a single immunizing strain of virus are likely to neutralize only very closely related viruses, a phenomenon known as type specificity. New studies suggest that antibodies directed at the fusion complex of gp41 may be particularly able to neutralize widely divergent viruses, which offers encouragement that induction of more effective neutralizing antibodies may be a realistic goal.

Antibodies constitute the first line of defense at mucosal surfaces, in the form of secretory IgA. Such secretory antibodies have been found in blood, saliva, and other body fluids of persons infected with HIV, but their potential role as a protective immune response in HIV-1 infection remains undetermined.

Antibody-Dependent Cellular Cytotoxicity (ADCC)
Another mechanism the immune system can use to limit the spread of infection is ADCC, which involves both cellular and humoral components. ADCC is a process whereby virus-specific antibodies bind directly to viral proteins expressed on the surface of infected cells, thereby sensitizing these cells for lysis by cells that bind to the exposed Fc portion of the antibody. The cells mediating this response are typically NK cells, which express the CD16 Fc receptor for IgG. Antibodies that can mediate ADCC have been identified in the majority of HIV-infected individuals; these are present soon after seroconversion and are maintained throughout the disease course. It has been postulated that ADCC may limit cell-cell spread of virus by providing an early cytotoxic host defense. ADCC may correlate with better clinical stage in children born to infected mothers, and ADCC titers have been shown to be higher in early stages of infection in some studies. However, the contribution of this immune response to protection from disease progression remains unclear.

Cytotoxic T Lymphocytes (CTL)
Cytotoxic T lymphocytes have been demonstrated to be one of the protective host defenses generated in response to a number of viral infections. CTL can kill virus-infected cells by recognizing viral protein fragments on the infected cell surface, where these proteins form a trimolecular complex with a surface HLA molecule and beta2 microglobulin. CTL recognition of this complex leads to lysis and elimination of the infected cell.

Although the hallmark of HIV-1 infection is the development of profound immunosuppression, extremely vigorous HIV-1-specific CTL responses have been detected in the peripheral blood of infected individuals. These responses are directed not only against the major viral structural proteins, but also against the reverse transcriptase protein and regulatory proteins such as vif and nef. These responses appear to be mediated predominantly by CD8+ lymphocytes, which recognize processed HIV proteins on the surface of infected cells in conjunction with HLA class I (A,B,C) molecules.

A protective role for CTL has been demonstrated in numerous experimental models of viral infection, and emerging data indicate an antiviral role for CTL in HIV-1 infection. High levels of HIV-1-specific CTL are detected in acute infection, and their appearance correlates with initial control of viremia. There is at least indirect evidence to suggest that the CTL response might indeed retard disease progression. For example, CD8+ lymphocytes from HIV-infected individuals can inhibit HIV replication in autologous CD4 lymphocytes in vitro. Similar inhibitory CD8 cells have also been identified in simian immunodeficiency virus (SIV)-infected macaque monkeys, and in vivo depletion of these cells leads to dramatic increases in viremia. Recent studies of adoptively transferred CTL clones indicate that these cells migrate to infected cells in vivo. Other indirect evidence that CTL may be important in retarding disease progression stems from studies quantifying HIV-specific CTL in infected persons. As clinical disease progresses, CTL numbers decline, which could help to explain the observed increase in viremia observed in later stages of illness. More recently, new techniques that allow for direct visualization of CTL by flow cytometry indicate that there is a negative correlation between CTL responses and viral load. The detection of vigorous HIV-1-specific CTL responses in long-term nonprogressors who control viremia is further evidence for a protective role of these cells.

Cellular Proliferative Responses
T cell immunity to viral pathogens consists not only of cytotoxic T lymphocytes, but also helper T cell proliferation and cytokine production in specific responses to viral antigens. This CD4+ proliferative response generally is triggered by recognition of viral antigen in association with class II (HLA-D) molecules on the surface of antigen-presenting cells. Cross-sectional data indicate a negative association between viral load and T helper cell responses to the Gag protein, providing supportive evidence for a critical role of T helper cells in controlling viremia. Strong helper cell responses are associated with strong CTL responses, and it is likely that the antiviral effect of T helper cells is mediated through enhancing effects on CTL responses. The majority of infected persons lack strong HIV-1-specific T helper cell responses, but persons with acute HIV-1 infection who are treated with potent antiviral therapy before seroconversion all develop strong Gag-specific T helper cell responses. This observation has led to the hypothesis that a significant proportion of HIV-1-specific T helper cells are lost in the earliest stages of infection as they become activated, perhaps because HIV preferentially infects activated CD4 cells.