Summaries of the Sixth Conference on Retroviruses and Opportunistic Infections:
April 15, 1999 6 minutes read
Summaries of the Sixth Conference on Retroviruses and Opportunistic Infections: Part III
CONFERENCE COVERAGE
Note: The following summaries represent a selection of papers from those presented at the 6th Conference on Retroviruses and Opportunistic Infections held on Jan. 31-Feb. 4, 1999, in Chicago, IL. It is important to recognize that some of these summaries are extracted only from the published abstract and it is possible that some of the material presented at the conference may have differed. The abstracts and posters, as well as other information presented at the conference, are available on the internet at www.retroconference.org. —Stan Deresinski, MD, FACP
Immunology
Evidence continues to accumulate confirming the crucial role of CD8+ T cells in the control of HIV replication. CD8+ T-cell depletion by administration of a monoclonal antibody is associated with a dramatic increase in viremia in SIV-infected macaques and rhesus monkeys. (Abstracts 252, 253.) The emergence of cytotoxic T lymphocytes coincides with clearance of virus during primary SIVmac infection in rhesus monkeys. (Abstract 254.) However, virus-specific CTL responses may select escape mutants in SIV-infected macaques. (Abstract 255.)
Two studies demonstrated that perforin expression by CD8+ T cells in lymphoid tissue is abnormally low. Although granzyme B levels are not impaired, the absence of perforin prevents the entry of this enzyme into target cells, thus, causing a significant defect in effector cytolytic T-lymphocyte (CTL) function. (Abstracts 62, LB3B.)
Using a fetal thymus organ culture system, it was found that progressors had lost 90% of their T-cell development capacity; long-term nonprogressors had lost only 68% of that capacity after eight years of infection. Sixty percent of patients had a more than two-fold increase in T-cell development capacity after six months of therapy and there was a significant correlation between this increase and the number of naïve CD4+ and CD8+ T cells in peripheral blood. (Abstract 22.)
T-cell receptor excision circles (TREC) are a by-product of intra-thymic T-cell selection; they represent excised DNA that is not replicated at the time of cellular replication. As a consequence, cells containing TREC are progressively diluted out over time. As a consequence, the quantification of TREC-containing T cells serves as a marker for thymus-derived naïve T cells. Administration of HAART is associated with a sustained increase in TREC-positive cells in lymph nodes and blood, indicating effective thymic production of naïve cells—good news for hopes of successful immune reconstitution (Star TREC, the New Generation?) (Abstract S42.)
After controlling for virological responsiveness, the rate of CD4+ reconstitution in response to HAART is diminished in older patients. (Abstract 335.)
HAART therapy is associated with reversion of the cytokine profile to a Th1 pattern as well as partially improved neutrophil and monocyte function. (Abstracts 333, 336.) Sustained control of HIV replication is associated with a reversion of the CD8+ T-cell repertoire to a polyclonal configuration from one with oligoclonal proliferations. (Abstract 342.) In a study of children receiving HAART, the greatest rise in HIV-specific CTL frequency was observed in those with incomplete viral suppression but increasing CD4+ T-cell counts. (Abstract 339.)
Successful HAART therapy is not associated with restoration of HIV-1 specific CD4+ T-cell responses. (Abstract 343.)
Both saquinavir and ritonavir reduced spontaneous in vitro apoptosis of CD4+ and CD8+ T cells of peripheral blood mononuclear cells obtained from HIV-infected PI-naïve patients. Each inhibited Fas induced CD4+ and CD8+ T-cell apoptosis. Apoptosis of uninfected cells was not affected. NRTIs did not affect apoptosis. The effect of the PIs appeared to be independent of their ability to inhibit HIV replication. (Abstract 349.)
Both ritonavir and saquinavir inhibit the in vitro responses of peripheral blood mononuclear cells from HIV-seronegative donors. (Abstract 345.) Indinavir inhibits anti-CD3 induced T-cell activation in vitro. It also, however, blocks cells in G0/G1 phase and induces IL-16 production, activities that may inhibit HIV replication. (Abstract 348.)
Neutralizing antibody increased after institution of HAART. (Abstract 352.)
Viral Eradication
With the exception of a few reports in patients treated very early in their infection, the bulk of evidence continues to indicate that complete viral eradication, if possible, is likely to require extremely long periods of treatment.
Prior to the start of therapy, the level of viral DNA expressing cells was approximately 2 log10 higher than was that of cells expressing viral RNA. Initiation of HAART was associated with a 0.7 log10 reduction in cellular HIV viral DNA within the first 10 weeks, probably due to loss of labile preintegration complex DNA. However, between 12 and 36 weeks of therapy, no further reduction in HIV viral DNA was found, indicating stability of integrated viral DNA in the face of HAART. (Abstract 158.) All 42 patients with undetectable viral loads for six months still had detectable cellular proviral DNA. (Abstract 397.)
A reservoir of "latently" infected T cells persists despite prolonged viral suppression as a result of HAART. A careful examination of blood mononuclear cells of patients with or without apparent suppression of viral replication detected the presence in both groups of two distinct populations of infected cells with regard to HIV replication—inducible and transcriptionally active. Neither decreased with increased duration of viral suppression. (Abstract 5.)
Examination of lymph nodes after two years of viral suppression (plasma HIV RNA < 500 copies/mL for at least 72 months) with IDV/ZDV/3TC found persistence of HIV RNA at a level essentially unchanged from that seen after one year of therapy. This observation suggests that the decay in viral RNA may have reached a plateau in this compartment. HIV RNA was less than 50 copies/mL in CSF from 15 of 15 patients while viral RNA was detected in genital secretions of three of 23 subjects. (Abstract 6.)
Fifteen (88%) of 17 patients on HAART for more than three years and with plasma HIV RNA less than 400 copies/mL had detectable HIV RNA in mucosal tissue obtained rectosigmoid biopsy with an assay with sensitivity of 10 copies. (Abstract 160.) The decay half-life of the latent HIV reservoir in patients with prolonged (2-3 years) viral suppression was estimated to be approximately six months. Examination of PBMCs and gut-associated lymphoid tissue (GALT) from patients with viral loads less than 50 copies/mL for two to three years found frequent evidence of proviral DNA and sequencing studies found evidence of evolution in envelope sequences consistent with ongoing replication. (Abstract 495.)
Eight patients with CD4 more than 500 cells/mm3 who had received d4T/3TC/ritonavir discontinued their therapy. Prior to discontinuation, all had plasma viral load less than 20 copies/mL and five had less than 5 copies/mL; tonsillar tissue had less than 40 copies/mg in five of five. Nonetheless, plasma virus rebounded in all eight patients at days 2-27. In three patients, the plasma viral load reached more than 0.5 log10 than prior to initiation of therapy. Phenotypic lymphocyte studies appeared to recapitulate those reported during primary HIV infection. Plasma viral load dropped to less than 20 copies/mL in all patients after reinitiation of therapy. (Abstract 629.)
An update on a previously reported patient from Berlin whose plasma viral load has remained undetectable after two treatment interruptions, the last for two years, was provided. There continues to be evidence of low-level replication competent virus in his lymph nodes and no evidence of neutralizing antibody. There is, however, evidence of a vigorous CTL response directed at p24 antigen. (Abstract LB6.)
Four patients started on HAART within 90 days of HIV infection with decrease in viral load to less than 500 copies/mL had episodes of discontinuation of antiretroviral therapy. In two patients with repeat episodes of nonadherence who finally discontinued therapy, plasma HIV RNA fell to undetectable levels and remained there for 21 and 14 months. Their CTL precursor frequency, which had fallen to low levels during viral suppression, was boosted during short periods of drug discontinuation associated with viral rebound. With final discontinuation of therapy, broad and strong CTL responses remained high. The third patient contained viral replication for four months after drug discontinuation, but CTL faded and virus rebounded. The fourth patient had, after discontinuation, only a low frequency of HIV-specific CTL and had an immediate viral rebound. (Abstract 256.)
Three patients with stable viremia were treated with HAART regimens containing hydroxyurea for three weeks, followed by therapy interruption for one week, then two cycles of three months each followed by treatment interruption and reinitiation as soon as rebound to more than 5000 copies/mL occurred. Mean rebound-free intervals were extended from seven days to 14 days and then to 37 days. A similar approach in SIV-infected macaques with treatment begun 28 days after infection was associated with progressively lower steady state viral load during treatment-free intervals. (Abstract LB5.)
The frequency of resting CD4+ T cells in peripheral blood carrying replication competent HIV in patients receiving intermittent rhIL-2 plus HAART is significantly lower than that in patients receiving HAART alone. No evidence of latently infected CD4+ T cells could be detected in three of six patients without detectable plasma HIV RNA receiving the combination. Lymph node tissue was obtained from two of these patients and no virus was detected in these. These two patients discontinued therapy and, at three-week follow-up, plasma HIV RNA could not be detected in their plasma. (Abstract 496.)
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