Studies on medical and immunological intervention in HIV-1 infection

Abstract

The very first HIV-1 infected patients who received antiretroviral combination therapy (HAART) were severely ill and had very low CD4+ T cell counts. We describe a group of severely ill HIV- I infected patients monitored for the first two years of their HAART. The patients were subdivided retrospectively into viral responders and viral low responders. Memory and naive T cells increased in both groups and membrane bound activation markers decreased. There were no clinical differences in number of deaths or HIV related events during two years follow up in the two groups. However after seven years there were clinical differences. Virological clearance was achieved in half of the patients in the original viral low responder group. Differences in adherence to HAART may explain the diverse outcome in the two groups.

This study argues for continued treatment with HAART in spite of viral failure and subsequent development of primary and secondary resistance mutations. If treatment with HAART is interrupted the CD4+ T cell count again decreases and viral load increases to the same level as before treatment. A group of HIV- I infected patients with a history of long time HAART, well suppressed plasma viral loads and recovered CD4+ T cell counts, were followed during long-term treatment interruption (LTI). We found that CD4+ T cell decrease during treatment interruption was an inverse reflection of CD4+ T cell increase during treatment. A close correlation between pre-HAART nadir CD4+ T cell counts (lowest ever), levels of CD4+ memory cells at the start of LTI and the duration of LTI, indicates that CD4+ T cell memory levels may not be fully recovered even after a long period of effective HAART, irrespective of absolute CD4+ T cells count reached during treatment.

HAART does not improve the specific immune response against HIV. Therapeutic vaccination would be a valuable addition to antiviral chemotherapy as immune stimulation potentially helps to reduce the need for antiretroviral drugs by strengthen or inducing new immunological responses. We monitored the long-term immune responses of HIV-infected patients immunized with HIV envelope rgpl60 before HAART was introduced.

HIV specific T-helper cell responses induced by immunization were maintained at high levels up to 7 years after the last injection. The addition of HAART in these patients did not alter this HIV-specific response but gave a profound reduction in viral load and increased total CD4+ T cell counts. Immunization with rgp160 was combined with HAART in another group of patients. As controls, patients treated with HAART only, were followed in addition to two groups receiving tetanus as a non HIV specific vaccine (one group with and one without HIV infection).

In keeping with previous rgpl60 immunization studies, we were able to demonstrate a positive effect of rgp 160 on CD4+ T cell count, measurable six to twelve months after the last immunization. The HIV-specific T cell response was maintained at very high levels up to two years in HAART treated patients, but not to the same extent in non-HAART treated patients, despite comparable or even higher CD4+ T cell levels during follow up. CD4 specific responses to recall antigens (tetanus toxoid and tuberculin) were boosted by the rgp 160 immunization. HIV specific immunization during HAART might thus induce responses potentially beneficial during a future planned treatment interruption.

In order to control HIV, effective CD4 and CTL responses are needed in addition to sufficient levels of neutralizing antibodies. Plasmid DNA vaccines can stimulate CTL by intracellular protein production, presented via the HLA class I pathway. They may also stimulate B cells to generate antibodies. We describe a study where DNA constructs encoding the rev, tat and nef regulatory HIV- I genes were given to asymptomatic HIV-1 infected patients on stable HAART and with undetectable viral load. The results were compared with a prior non-randomized study where the same genes were given separately in a ten fold lower total dose to patients with similar CD4+ T cell levels but not on HAART. New HIV-specific proliferative responses were found in all immunized patients who lacked this response before immunization. The specific cytolytic capacity decreased in the placebo group but not in the immunized groups. We did not find that HAART per se was important for the immediate response to the chosen DNA plasmids, in patients with comparable CD4+ and CD8+ T cell levels, even though the total DNA dose was ten folds higher. Since both nef and tat have immune suppressive activities, these properties may have been more prominent in a combination of the genes in a higher dose.

We have clinical evidence that long-term antiviral treatment causes viral suppression and clinical benefits in both viral responders and low-responders. An important variable for prediction of successful interruption of treatment appeared to be retained CD4+ memory cells, directly correlated with nadir CD4+ T cell count. HIV immunization together with antiviral treatment enhanced the magnitude and duration of new HIVspecific immune responses. Immunization with HIV antigens alone has improved short-term survival and almost always induces new HIV-specific T cell responses. This shows that new memory cells can be induce by vaccination in the chronic phase of infection, which should permit extended treatment interruption.