Greater understanding of the role of HIV-specific immunity remains fundamental to current and future therapies to prevent and treat HIV infection. The induction of HIV-specific immunity in seronegative individuals might involve similar or different effector cells of the immune system compared to individuals who are infected and maintain a reservoir of latently infected cells on or off antiviral drugs. This short review will focus on recent understanding of HIV-specific immunity in HIV-infected individuals. Specifically, the role of the CD4+ T helper cell in HIV-specific immunity will be addressed.

CD4+ T cells are acknowledged as one of the key components of the immune system that are preferentially infected and depleted over time in HIV infection (1). These cells contain various coreceptors and are involved in key host-defense functions including, but not limited to, the release of cytokines and chemokines, and thus they are pivotal orchestrators of the antiviral attack against HIV. Very early in HIV infection, prior to a decrease in absolute CD4 cell number, functional defects in HIV-specific CD4+ T helper cells become apparent, including the inability of CD4+ peripheral blood mononuclear cells to proliferate in response to HIV antigens (2, 3). The notable exception to this natural history are studies of individuals with long-term clinical nonprogression, who have been observed by multiple groups as having strong T cell proliferation to core HIV proteins (4-8). These studies also suggest that the more genetically conserved parts of HIV-1 (i.e., gag) might contain important epitopes recognized by the immune system and involved in the control of HIV (9).

Using new immunologic assays, studies now suggest that in chronic HIV infection, virus-specific CD4+ T cell clones are detectable and thus are not completely depleted (10). However, the frequency of HIV-specific cells observed might not be adequate to provide antiviral T helper function against HIV. This is exemplified by a recent study which demonstrated that although HIV-specific clones are detectable in terms of their ability to produce interferon g, T cell proliferation to HIV is suppressed, particularly during periods of viral replication (5). Consistent with this observation is an earlier report that suggested that although HIV-specific interferon g induction might be detectable, the loss of lymphocyte proliferation was associated with progression of disease (7). Other groups have also recently reported this discrepancy between the frequency and proliferation of HIV-1-specific CD4+ T cells (11).

One possible explanation is that newer immune assays such as ELISPOT or intracellular cytokine measurements are more sensitive, compared to the lymphocyte proliferation assay, in their ability to measure HIV-specific T cells. Thus, having a low frequency of HIV-specific clones might not be sufficient to provide adequate functional T helper activity. In contrast, at higher HIV-specific CD4+ T cell frequencies, such as those observed with therapeutic immunization or in clinical nonprogressors, there appears to be a correlation between the frequency of HIV-specific T cells producing interferon g and T cell proliferation (12, 13).

Taken together, these studies suggest that there might be a threshold frequency at which HIV-specific cells are able to proliferate and can perform their important role as T helper cells. Importantly, these recent studies suggest the existence of detectable HIV-specific memory clones in chronic infection, which were previously thought to be completely lost. Therefore, the finding that HIV-specific cells might not be completely depleted lends support to strategies that focus on augmenting these cells in order to induce anti-HIV immunity.

Various approaches are being examined to treat the immune dysfunction characteristic of HIV infection. More potent antiviral drug therapies have had a dramatic acute impact on mortality and morbidity by lowering viral replication, but they concomitantly decrease antigenic stimulation (14). Thus, highly active antiretroviral therapy (HAART) appears to prevent further immunologic decline with the acute restoration of immune function against opportunistic infections. But T helper proliferative immune response against HIV might not be acutely restored with HAART in a majority of individuals with chronic HIV-1 infection (15-19). It is likely that in these individuals CD4+ T cell clones have already been depleted to low frequencies. In contrast, with earlier treatment with HAART, when the frequency of CD4+ T cells might be higher, it might be possible to restore immune function, including the CD4+ T helper response. For example, restoration of T helper lymphocyte proliferation has been observed in subjects treated with HAART during the primary phase of HIV-1 infection (20-22).

In addition to HAART, a number of other strategies have been examined in an attempt to reconstitute HIV-specific CD4+ T cell immunity. Some studies of antiviral structured treatment interruptions (STIs) in chronic infection have shown transient increases in HIV-specific lymphocyte proliferation and interferon production (23-25). Interestingly, some studies of STIs have noted control of viremia in a small number of subjects who display strong lymphocyte proliferation to core gag proteins (26).

An alternative strategy has been to augment HIV-specific immune responses with therapeutic vaccination. An enhancement of T helper immune responses to core proteins has been observed in studies of therapeutic immunization using a gp120-depleted antigen (Remune) (27-30). In addition, other therapeutic vaccine approaches using envelope or core antigen constructs have also demonstrated an effect on T helper immune responses (31-34). Perhaps most importantly, the magnitude of lymphocyte proliferation in subjects on HAART, augmented with therapeutic immunization, might be comparable to that observed in clinical nonprogressors (35, 36). It should be noted that many parameters might have an impact on the level of induction of HIV-specific immune responses after therapeutic immunization. For example, low viral load, high CD4, and HAART use prior to immunization have been observed to be associated with a better HIV-specific T cell proliferative response to immunization (37-39). Also, time since seroconversion and the availability of HIV-specific T cells are factors that most likely have an impact on the ability of therapeutic immunization to induce T helper lymphoproliferative responses.

A recent report also provides some important insights into the potential importance of disease stage in the ability to stimulate effective HIV-specific immunity. This study examined a small number of HIV-infected subjects, a majority of whom were infected for more than 10 years. It was observed that in these subjects, HIV preferentially infected virus-specific CD4+ T cells (40). The authors concluded that caution should be exercised with STIs, which might stimulate HIV-specific CD4+ T cells.

Indeed, an enhancement of CD4+ T cells, whether it be through cytokines such as interleukin-2, STIs, or therapeutic vaccination, should be studied in subjects who maintain a relatively low frequency of CD4+ infected T cells overall (41). But it is unlikely that enhancement of HIV-specific immunity in early disease or in subjects on antiviral drug therapy would result in any unwanted effects, such as increases in viral replication or disease progression. Two preliminary studies of STIs support the notion that there is little deleterious effect of STIs in subjects with low viremia and high CD4 cell counts (42, 43). Furthermore, a most recent review of HIV therapeutic vaccine trials does not suggest that an enhancement of HIV-specific immunity is associated with disease-potentiating effects (44). On the contrary, a trial therapeutic vaccination (Remune) in subjects on antiviral drug therapy revealed a positive impact on delaying virological breakthrough, which correlated with CD4+ T cell helper and CD8+ T cell responses induced by vaccination (45). These results are also consistent with observations that therapeutic vaccination in nonhuman primates, which stimulated HIV-specific immunity, can have a positive effect on lowering viral load (46, 47).

In summary, the virus-specific CD4+ T cell is a key player in the immune attack against HIV. New, more sensitive measurements of HIV-specific CD4+ T cell frequencies suggest that these cells are not completely depleted but are detectable in chronic HIV infection. Thus, the strategy of stimulating these clones with therapeutic vaccination and/or STIs becomes an important area of research and clinical development. Additional insights into the host factors that have an impact on the response to therapeutic immunization and/or STIs are warranted in order to optimize these approaches. Greater understanding of HIV-specific immunity in infected individuals should translate into additional therapeutic options for HIV-infected individuals and possibly also provide a better understanding of the immune requirements for an effective preventive HIV vaccine.

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