Dutch, U.S. Researchers Report Partial Success with Flushing Strategies; Plan to Suspend Treatment in Patients
Halls abuzz with the 'c' word
Late every August, the once-and-future greats (and some not-so greats) of AIDS research pay homage to HIV co-discoverer Robert C. Gallo at the annual laboratory meeting once, in palmier days, hosted in Bethesda by the NCI Laboratory of Tumor Cell Biology, now hosted by the Institute for Human Virology (IHV) and held at the tourist-friendly Hyatt Regency Harborside in glamorous, sweltering Baltimore, Maryland. Mark Harrington attended the first four days of the week-long research gab-fest. Some highlights:
Update on the Pan-American Pandemic. Fernando Zacarias of the Pan American Health Organization (PAHO), a unit of the World Health Organization, delivered an update on the epidemic in the Caribbean and Latin America. PAHO estimates that 1.3 million people are infected in Latin America, and 300,000 in the Caribbean. The epidemic affects different populations in different countries.
Zacarias stated that AIDS cases may be declining in Brazil. The government there is spending $700,000 to provide antiretroviral treatment, including protease inhibitors, to 50-60,000 people with HIV there. He discussed a gradient of HIV clinical management, dependent on a country's given health care infrastructure, the quality of usage, etc. It would begin with HIV counseling and testing, ancillary care (diarrhea, pain management, aspirin, etc.), scale up to opportunistic infection treatment (especially for TB), sexually transmitted disease treatment, and prevention of vertical transmission, and finally culminate in comprehensive antiretroviral therapy. Obviously different countries have different resources.
Is Subtype HIV-1C More Virulent? Max Essex of Harvard presented an unconvincing paper attempting to demonstrate that HIV-1 subtype C, which is increasingly prevalent in parts of Africa, is more virulent than other subtypes and more easily transmitted heterosexually. He claimed that some C subtypes have additional long terminal repeat (LTR) and NF-kappa-B viral transcription promotor regions than other strains. This would, he claimed, enable subtype C to grow faster than other strains. However, "there are different Cs; all Cs are not alike."
Laurie Garrett, behaving just like television's relentless Murphy Brown, approached the microphone and decimated Essex's paper with a historical/epidemiological explanation for the greater preponderance of subtype C in the new South African pandemic. Patterns of guerrilla travel, social disruption and migrant labor led to HIV transmission along supply routes, leading to a dramatic increase in HIV in southern Africa. The fact that it was subtype C was just a matter of chance.
Accelerating Decay of the Third Compartment. Several teams are wasting no time exploring immuno-stimulants which may accelerate decay of the third compartment (the pool of 100,000 to 1 million resting, latently infected CD4+ T cells which represent the current principal stumbling block to total eradication of HIV in the body). At NIH, Cliff Lane and Tony Fauci took 13 patients on HAART who had maintained a viral load below the limit of quantification and administered relatively high-dose interleukin-2 (IL-2). IL-2 is postulated by some to activate resting T cells, although some (e.g., Siliciano) maintain that the resting cell population does not express IL-2 receptors. In any case, Fauci reported that provirally-infected cells could no longer be isolated from 3 of the 13 IL-2+HAART recipients, even when as many as 300 million cells were extracted. Obviously the "limit of detection" for eradication experiments will be compromised by the impossibility of sampling such large numbers of cells.
Joep Lange of the University of Amsterdam administered an even more daunting regimen of five antiretrovirals plus IL-2 and the mouse monoclonal antibody OKT3, which targets and activates all the body's T lymphocytes through the CD3 receptor. The result is a clinical condition resembling toxic shock, as all the cells release pro-inflammatory cytokines and many die of apoptosis. The hope was that the coadministered HAART would prevent the viruses produced by waking latently infected cells from infecting another generation of cells. While the patients became very sick (requiring admission to the intensive care unit), infectious virus could no longer be cultured from two of the three. One declared himself cured and disappeared from follow-up. However, in both Lange's and Lane's experiments no one has yet to go off HAART. Lane will start enrolling a study at NIH this fall in which anyone who has maintained a CD4 count below 5 copies/mL for over one year will have their antiretroviral therapy terminated. Researchers will then follow the brave volunteers for evidence of viral re-emergence (this approach does not seem to make sense unless the patients have received immunostimulatory therapy). Researchers were reluctant to use the "C-word" in their presentations, but the halls were abuzz with the slightly surreal gossip about very toxic, potentially fatal, possibly curative regimens.
Frequent HIV Reinfection Demonstrated in Chimpanzees. Addressing an issue vexing HIV treatment and prevention, Pat Fultz of the University of Alabama at Birmingham (UAB) presented compelling evidence that infection with a primary HIV strain does not prevent subsequent reinfection by another strain in the chimpanzee model. In some animals, both strains were readily detectable at later time points, while in some cases the earlier strain (or strains, in one animal reinfected twice) predominated. The ability to detect superinfection depends on using strain-specific PCR primers (which is not done with standard commercially-available viral load assays used in humans). This work has chilling implications for the dissemination of drug-resistant HIV strains among indivudals already infected. Superinfection is not necessarily detectable by increasing antibody titers, suggesting that there is not always a "booster effect." Fultz achieved 100% (9/9) superinfections within viral clades, and 9/13 between clades.
Estimated Cost of Providing Antiretroviral Therapy to the 'Developing' World