Immune assays have generated several key findings about HIV pathogenesis: The selective depletion of naive CD4 T-cells is a hallmark of progressive HIV disease. Chronic immune activation results in increased proliferation and apoptosis rates, which may play a major role, perhaps overshadowing the contribution of the direct cytopathic effects of HIV and/or cell-mediated destruction of HIV-infected cells. The possibility of impaired thymic production, and the prospects for stimulating the thymus to compensate for CD4 loss, represent important but contested areas of research. HIV-specific CD4 and CD8 T-cell responses, which are significantly impaired in untreated progressive HIV disease, continue to decline during the course of antiretroviral therapy. Studies of interrupted suppressive therapy suggest that periodic antigenic stimulation may temporarily awaken these responses.

Research indicates an association between HIV infection and multiple forms of immune dysfunction, processes that may operate independently or synergistically. Still other research has focused on the innate immune response and a perceived shift in the course of HIV infection from a predominantly Th1-type response (where effector CD4 cells prime cell-mediated immunity, including CTLs) to a Th2-type response (in which CD4 cells direct their support to humoral immunity, stimulating B-cell and antibody production). As of yet, however, there is no "smoking gun" revealing the precise mechanism(s) of HIV pathogenesis. Pools of consensus ebb and flow around various hypotheses, and while research has led to a range of proposals for therapeutic strategies, no new agents have been approved to treat the immune system rather than the virus.

Immunity research has had its most direct impact on clinical practice by justifying and guiding the treatment of acute HIV infection with a combination of HAART and treatment interruption. This approach has yielded promising data, which in turn has influenced thinking on vaccine development, but a demonstration of long-term clinical benefit is years away. Moreover, such early-stage treatment could only benefit the relative few who are diagnosed very soon after infection, and are willing and able to begin treatment immediately.

Ultimately, the applicability of in vitro assays to in vivo immune system dynamics and virus-host cell interactions must be questioned. For instance, the extensive research into the mechanisms of HIV-mediated apoptosis has generally been conducted in vitro, yet there is ample evidence that in vitro cell cultures can have different requirements for activation, signal transduction, and transcription.

Furthermore, it may be questioned if demonstrating that HIV affects the induction of apoptosis would necessarily mean that this mechanism plays a role in disease progression. Would anti-apoptotic agents in development to treat other diseases have any benefit in HIV treatment? Perhaps questions about how and why cells are dying in HIV disease are less important than looking at which cells are dying -- too many of the useful cells and not enough of the infected or functionally impaired cells. Or perhaps lowering activation rates or increasing thymic output would be more effective in countering T-cell depletion.

Immune assays and the researchers who use them have become increasingly sophisticated at answering certain questions about the immune system and T-cell dynamics: What kind of cells? How many? What are they doing? Are they functional? However, these assays are only valuable for the kinds of questions they know how to answer; the whys and hows of pathogenesis and immune reconstitution can only be addressed through the vicissitudes of interpretation and speculation. The models or assumptions already in place at any given time tend to guide the research, and preconceived assumptions have certainly been overturned more than once in the history of HIV research. Yet the gradual accumulation of data inevitably shapes the scientific consensus on what we can say we know about HIV; certain theories are judged more or less consistent with the evidence, as other hypotheses and lines of inquiry gain support or are ruled out. Finally, as our investigational tools continue to evolve, perhaps the advent of research informed by genomics will afford us the luxury of worrying that our ability to ask questions will increase faster than our capacity to make sense of the answers.