Harnessing the Immune System to Fight HIV
- Harnessing the Immune System to Fight HIV Infection (WeOrA197)
Authored by Bruce Walker
Non-abstract driven session
The presentations in this session were quite rushed due to the 15-minute time limit. Bruce Walker, well known for his work examining treatment interruptions in the setting of treated primary infection, took the speaker's prerogative and changed the focus of his presentation to "why the immune system loses control of HIV replication." The stimulus for this discussion was one of the original cohort patients participating in Dr. Walker's study on treatment interruptions (STIs).
The results of the original cohort were briefly summarized, highlighting that 10 of the 14 study subjects were still off of treatment and eight of those had levels of viremia below the predicted average for the MACS cohort. The major parameter associated with the ability to maintain a low viral level off treatment was the presence or development of increased CD8+ cytotoxic response (CTL-stimulated by cycles of treatment followed by treatment interruptions).
Dr. Walker discussed one person in the study. Study subject X was off therapy with a stable viral load after several cycles of treatment and several treatment interruptions. At around day 290, the patient's viral load suddenly increased and the CD4+ T-cell count began to fall, despite prior documentation of increased CD8+ T-cell associated CTL response. The patient's HIV specific CD4+ response, documented to be present during the period of stable viremia, also was noted to drop.
Since this scenario had not been observed in other subjects in the cohort, extensive analysis of the virologic and immunologic features of the case were undertaken. No change in the sequence of the dominant epitope has been found but mutations in regions outside the dominant CTL directed epitope were noted. That observation led to an analysis of the viral clade and similarity between the original viral isolate (obtained during the primary infection) and the rebounding virus.
The original virus was a clade B virus (typical for the U.S.) while the rebounding viral isolate differed by 12 percent yet was also a clade B virus. That ancestral analysis led the investigator to conclude that the patient became super-infected with another clade B strain during the treatment interruption after an episode of anonymous unprotected sex. Isolates of the original clade B virus could not be isolated from the plasma during the virologic rebound but both clade B strains could be isolated from circulating peripheral blood mononuclear cells. The CTL activity against the new clade B isolate was decreased suggesting that the protection afforded against the original B strain was not cross protective against the new clade B strain.
Although just a case report needing confirmation, this case has obvious and ominous implications for the potential for immune control of HIV replication and vaccine development. Super infection with another clade B strain in a patient whose immune system was controlling the original clade B strain is very disconcerting. Previously, there was concern about whether a candidate vaccine representing one clade or strain would have activity against other strains or clades. Now the concern seems to extend to more related viruses even in the setting where good anti-HIV immunity has been stimulated. There are also serious public health implications, which include the issue of super infection with additional strains of HIV and the infectiousness of patients during treatment interruptions. The audience had come to hear Dr. Walker give a talk about how the immune system could be fostered to control HIV replication yet heard how HIV-specific immunity failed to protect a patient against infection with a virus of the same clade. The spirit of the audience seemed to sag noticeably as the implications of the report sank in. If similar cases are observed, HIV vaccine research may have suffered a very serious setback.