Immunization to the Fore
Long Languishing in Shadow of the Antiviral Quick Fix, Immune Based Therapies Are Called to Center Stage
How to refortify the immune system
The twilight of eradication may herald a new dawn for HIV immunology research, which has been largely overshadowed by advances in antiretroviral therapy over the past three years -- and its now haunting mantra of, ‘It’s the virus, stupid.’ At a recent meeting at Robert Gallo’s Institute for Human Virology (IHV), 60 HIV immunologists from the U.S. and Europe enthusiastically looked forward to 1998 as the year of the return to the immunocentric disease modeling that characterized mainstream HIV research during the 1980s and early 1990s. Craig Sterritt prepared this report for TAGline.
The meeting, entitled "Immune Function and Surrogate Markers: Setting the Goal Line," was charged with taking stock of the current state of HIV immunology and immune-based therapy (IBT) research and charting the course ahead for the development of new therapeutic interventions. Key to the evaluation of new immune-based therapies is the identification of surrogate markers useful in evaluating the biologic activity(ies) -- and clinical efficacy -- of the therapies in question. Appropriately, Robert Siliciano convened the scientific sessions with a review of his recent findings concerning the "third compartment" of viral decay -- namely, long-lived, quiescent memory T-cells harboring integrated HIV DNA. Many feel that Dr. Siliciano's reports, along with corroborating ones from other labs, have put the kibosh on the timely eradication hypotheses promulgated by David Ho and others. In essence, it now seems unlikely that HAART will be able to effect viral eradication within 10 years -- let alone 2 or 3.
Although the new highly active antiretroviral regimens may not result in viral eradication, longitudinal immunophenotypic and functional studies have demonstrated that they can lead to marked improvements in diverse parameters of immunocompetence. Two groups -- one led by Brigitte Autran in Paris and the other Michael Lederman of Case Western Reserve in the U.S. -- have been looking at what happens to the immune system following the initiation of HAART. They are finding that the immune systems of people who achieve and maintain undetectable viral loads on HAART gradually begin to normalize and look more like the immune systems of HIV-negative people and HIV-infected long-term non-progressors (LTNP). Specifically, T-cell counts go up, markers of immune hyperactivation diminish, and T-cell subsets, including CD4+, CD8+, memory and naïve T-cells, each type of which is disproportionately either increased or reduced during HIV infection, trend toward a more normal state. These effects are believed to be the immunologic correlates of HAART's clinical effects: increased resistance to infections, reduced disease progression, and improved survival.
Most significantly, Dr. Autran reported the recovery of previously 'lost' cellular immune responses to recall antigens (i.e., specific pathogens, such as mTB). Dr. Fred Valentine of NYU also reported the return of immune reactivity to Candida and other recall antigens in some patients receiving HAART. Citing an example of a patient with undetectable T-cell responses to PCP who experienced PCP after discontinuing prophylaxis consecutive to substantial CD4+ T-cell increases on HAART, Dr. Valentine suggested that the immunologic yardstick used to measure these responses -- the lymphocyte proliferation assay (LPA) -- may be a useful clinical tool for determining whether to continue or stop prophylaxis for particular infections in individual patients. Additional studies of this immunologic marker will be required, however, as Dr. Lederman presented evidence that improved LPA responses to recall antigens may be transient. His group observed improved antigen-specific LPA responses after 12 weeks of HAART, but noted no significance difference from baseline at 48 weeks.
Even with the return of improved general and pathogen-specific immunity, what has been observed to date can only be referred to as partial immune reconstitution. This is because in some cases (but not all), when HAART stops working, the immune system rapidly reverts to its pre-HAART state: T-cells decline and other immune markers become skewed again -- i.e., HIV disease progression continues. Although HAART can provide the immune system with a period of significant recuperation, this temporary cease fire apparently does not lead to improved HIV immunity. As Dr. Autran explained at the IHV meeting, even after 2 1/2 years, her studies have yielded no evidence that HAART can restore immune responses associated with improved control of HIV, such as those seen in HIV-infected LTNP (e.g., detectable LPA responses to p24 antigen; see TAGline, January 1998).
With regard to full immune reconstitution, what could ideally be accomplished is that new (immune-based) therapies could be used to refortify patients' immune systems against HIV and other pathogens while their HIV levels are being suppressed by HAART. In this way, if HIV returns -- if people on HAART experience "virologic failure" -- patients' immune systems would be better equipped to control HIV in the presence of waning antiretroviral efficacy. If we position contemporary IBT research within this context, HAART may be seen to provide a window of opportunity during which optimal host immunity to HIV (and other pathogens) may be restored. As Dr. Valentine succinctly stated at the IHV meeting, "my definition of immune reconstitution is bringing back an immune system that can respond to and better control HIV."
It is possible that immune reconstitution defined as such can occur, at least to a moderate degree, in some people treated with HAART. It is clinically apparent, although the phenomenon has not been captured in either Dr. Autran's or Dr. Lederman's studies, that some people who "fail" HAART continue to do well immunologically and clinically. These cases are typified by stable or increasing CD4 counts in the presence of virologic breakthrough, wherein viral load becomes detectable but does not return to pretreatment levels. It is entirely unknown why this occurs, what the immunologic basis for it is, or whether such an anomalous rising viral load/rising T-cells state is durable. It is possible, however, that the situation marks an advanced degree of immune reconstitution achievable with HAART, but as yet unelucidated by clinical studies. Dr. Valentine and others are eagerly recruiting immunologically stable/virologic breakthrough patients in order to characterize potential immunologic determinants of this phenomenon (see footnote below).
With regard to therapeutic interventions, the future of IBT research in HIV disease will concentrate on the induction of potent anti-HIV and anti-OI immune responses in patients who experience partial immune reconstitution on HAART. Immediate research is focusing on the use of therapeutic vaccination with HIV antigens. As TAGline reported in January, strong anti-HIV CD4+ LPA responses have been documented in monkeys inoculated with a DNA vaccine. A preliminary clinical study has demonstrated that this approach is safe for use in humans. At the IHV meeting, Ron Moss of Immune Response Corporation reported that vaccination with the "Salk" HIV-1 immunogen induced strong CD4+ LPA responses to the immunogen itself and to purified p24 antigen derived from the immunogen. Cross-clade (clades B and E) anti-HIV LPA responses were also documented in a small study by Dr. Moss and colleagues. In addition, Dr. Moss reported significantly increased p24 antigen-induced beta-chemokine production (RANTES, MIP-1alpha and MIP-1beta) following immunization with the Salk HIV-1 immunogen. Finally, a team of NCI researchers have announced the development of an inactivated HIV immunogen that retains the structural and functional properties of HIV's envelope proteins. All told, numerous groups around the world are preparing to begin vaccinating HAART-treated patients with HIV antigens and/or anti-OI antigens. Initial trials will focus on the ability of interventions to induce or augment antigen-specific LPA responses, cytotoxic T lymphocyte responses, and beta-chemokine release.
What remains to be fully elucidated is how improvements in specific immunologic tests (such as those cited above) can be used to predict the clinical efficacy of a therapeutic intervention. In spite of its go-getter title, "Setting the Goal Line" did not effectively push forward the cause of identifying expedient methodologies for qualifying and quantifying immune reconstitution. To date, the only immunologic marker that has been validated as a surrogate for clinical efficacy is the CD4+ T-cell count.
There was conjecture at the IHV meeting that these anecdotal reports may be found to reflect the recovery of robust anti-HIV cellular immune responses, such as those seen in LTNP and in acute seroconverters treated with HAART by Bruce Walker and colleagues at Harvard and Mass General (see TAGline, January 1998). These responses -- namely, CD4+ T-cell proliferative responses to HIV antigens -- are typically lost soon after initial infection. Conventional wisdom maintains that this is a consequence of the preferential elimination of activated anti-HIV CD4+ T-cells by HIV during the earliest phases of infection, and that this 'clonal depletion' is manifest as pertubations in the T-cell repertoire. Theoretically, it is possible that with long-term suppression of viral replication, immune normalization may extend to include the correction of biases in the T-cell repertoire. This would occur as naïve T-cells, with the capacity to engender new clones of potent anti-HIV T-cells, return to the blood and tissue of people with HIV. Both Dr. Autran and Dr. Lederman have reported quantitative and proportional increases in naïve T-cells following prolonged suppressive antiretroviral therapy. Indeed, Dr. Autran has documented some degree of correction in the T-cell repertoire, although the immunologic and clinical significance of these findings remains unclear.