Can HIV be Eradicated?: Report on Dr. David Ho's Presentation

David Ho, M.D., the leading HIV researcher in the United States, who was recently recognized by TIME magazine as Man of the Year for his contribution to the understanding of the pathogenesis of HIV infection, stated at the opening session of the 4th National Retrovirus Conference in Washington, DC that despite the fact that no patient with HIV infection has had the virus eradicated, he remains optimistic that this may be possible with the use of potent antiretroviral combination regimens, if taken early enough during infection.

Ho described the latest information emerging from his laboratory, which indicate that there are at least two phases in the decay of viral activity noted when a patient is treated with protease inhibitor containing regimens. Free virions decay with a half-life of approximately 6 hours, while the half-life of productively infected cells is in the neighborhood of 1.5 days. The second phase decay of viral activity is much slower, approximately 2 weeks, and reflects the decline of viral activity in another pool or compartment, that of latently infected lymphocyte and macrophages. Ho proposed that the decay characteristics of these additional compartments will determine how long therapy with potent combinations may need to be administered to totally eliminate the virus.

In a clinical study of 8 chronically infected patients treated with the combination of nelfinavir, AZT and 3TC, all patients had plasma viral load and peripheral blood mononuclear cell infectivity titers below the level of detection (100/ml) after 8 weeks of therapy. The decay characteristics of the second compartment (macrophages) had a half-life of 14.4 days whereas that of the latently infected lymphocytes had a half-life of 8.5 days. Proviral DNA remained detectable after 120 days of treatment at a level of approximately 1000 copies/ml, yet may represent noninfectious virions residing within cells, since no patient had culturable virus. Using these data, Ho predicted that time of elimination of HIV infection was most likely determined by the size of each compartment; estimating a free virus pool size of 10⁹-10¹², he estimated that the time to elimination of free virions, productively infected lymphocytes and macrophages would be between 2.3 and 3.1 years.

One additional compartment which Ho discussed was the one which contains virions trapped within follicular dendritic cells, which probably behaves similar to that of infected macrophages, as an experiment conducted by Noterdam et al. examining the turnover of HIV RNA in tonsillar tissue suggested a similar half-life for HIV RNA, of approximately 14 days. Caveats which should be taken into consideration include potential contributions from small, unknown compartment with slower decay characteristics including hidden sanctuary sites, such as the central nervous system, and recombination between defective proviruses.

Another clinical experiment which Ho described as "Proof of Principle" involved 24 patients who were treated within 90 days of seroconversion with either AZT, 3TC and ritonavir or AZT, 3TC and indinavir. Four patients were not evaluable because the patients left the study due to noncompliance or adverse effects; of the 20 remaining, one was briefly noncompliant with therapy. After 5 months of therapy all patients had undetectable levels of HIV RNA in the plasma (< 100 copies/ml, except for the one briefly noncompliant patient. Similarly, all but one had nonculturable virus from their peripheral blood mononuclear cells. Ho also looked at the semen of the patients for the presence of HIV RNA (both unspliced and multiply spliced RNA) and HIV DNA. Unspliced RNA reflects ongoing replication. He was unable to find either spliced or unspliced RNA, but did find proviral DNA in the seminal fluid mononuclear cells. He also looked for the presence of virus in lymphoid tissue obtained from rectal, sigmoid and descending colon biopsies using culture techniques, in-situ hybridization and PCR. Again he was unable to find HIV RNA using in-situ hybridization, yet found 3 of 5 patients had unspliced messenger RNA when he used the PCR technique (100-1000 copies/ml), which he attributed to residual trapped RNA within the lymphoid follicle. All cultures from the lymphoid tissue were negative for infectious virus. Ho concluded that overall these patients had very little HIV remaining, as determined by these very sensitive techniques.

He also reported on the immune responses seen in these patients, and showed that there was a blunting if not lack of production of gp120 and p24 antibodies as compared to untreated patients. In 7 cases there was also an absence of fresh unstimulated cytotoxic T lymphocyte (CTL) response in their peripheral blood mononuclear cells. Ho plans to continue triple therapy in these patients for 2-2.5 years, and to continue to biopsy their gut tissue as well as lymph nodes or tonsils. He also plans to study their cerebrospinal fluid to assess the presence or absence of virus in the central nervous system. He does not plan to stop therapy yet, as he does not believe enough time on treatment has elapsed. Ho advised to remain optimistic, but to avoid "unwanted triumphism"; he commented that in regard to the treatment of HIV infection, "it is neither black nor white; we must paint a situation in the proper shade of gray." Although he couched his entire presentation with many caveats and extreme caution, the compelling data noting absence of replicating virus in both chronically and recently infected patients hopefully will motivate most infected persons and their providers to accept early intervention with potent triple combination regimens as the therapy of choice in most if not all circumstances.