The Body Covers: The 7th Annual Clinical Care Options for HIV Symposium
HIV Pathogenesis: Can This Disease Be Cured?
Dr. John Coffin, from Tufts University Medical School, began the discussion of HIV pathogenesis by pointing out that a great deal of viral evolution, with multiple generations of virus, takes place during what was once called the "latency period." Studies of SIV-infected monkeys have shown considerable genetic diversity within 6 months of infection. There is no true latency: persistence of virus is a result of a constant cycle of active viral replication, infection of new cells, clearance of those cells with cell death, and cell replacement. Infected cells can be (1) productive (turning over rapidly with release of new virions), (2) chronically or latently infected (turning over more slowly), (3) or may harbor proviral DNA without being productive of new virus.
When suppressive antiretroviral therapy is initiated, infected productive cells, which account for over 90% of infected cells and which contribute 95-99% of the viral load, are cleared quickly because of their half life of approximately 1.6 days. This leads to the so-called "alpha slope," the large decrease in viral load seen within the first four weeks of therapy. The "beta slope," the subsequent gradual decline in viral load, is due to the decrease in infected latent cells, whose half-life is on the order of 20 days and which contribute approximately 1% of viral load. There may also be other populations of infected cells for which decay occurs even more slowly. Nonproductive cells containing defective remnants of viral DNA turn over even more slowly, with a half-life of approximately 100 days. These cells, however, do not contribute to plasma viral load.
The hypothesis that eradication can be achieved if suppressive therapy is given for a long enough period is based on the assumption that productively infected cells could be eradicated after 38 to 54 days and latent or chronically infected cells could be eradicated within 400-600 days. Nonproductive cells do not contribute to viral load. It is estimated that it would take 7 to 10 years to eradicate them, assuming a half-life of 100 days. It is not known whether these cells could be capable of rekindling infection. Clearly, this would have enormous implications on the feasibility of eradication.
Of course, the only way to test the eradication hypothesis will be to stop therapy in patients who have been maintained at undetectable levels for long periods of time and who lack detectable virus in compartments other than blood (lymph nodes, CSF, etc.). While there is a theoretical risk associated with stopping therapy, by stopping all drugs completely and simultaneously, there should be little selective pressure promoting the formation of resistance mutations. In contrast, "stepping down" therapy by removing drugs in a staged fashion might be more likely to promote resistance and treatment failure.
The plasma viral load reflects the number of infected cells, and is a direct measure of the amount of damage HIV is doing. Dr. Coffin repeated his now famous train metaphor. If a train is speeding toward a broken-down bridge, the CD4 count reflects the distance from the train to the imminent disaster, while the viral load reflects the speed at which the train is traveling.
Drug resistance is the primary cause of treatment failure. To date, no antiretroviral agent has been developed to which HIV cannot become resistant. In some cases, a single mutation leads to resistance (e.g., 3TC, nevirapine); in others, multiple mutations are required (e.g., protease inhibitors). These mutations are counterselected if there is no drug providing selective pressure, because mutant strains are "less fit" than wild-type, or sensitive virus. Thus the "steady state" is a balance between mutation from wild type to mutant and from mutant back to wild type. It can be thought of as the mutation rate divided by the cost of the mutation to the virus, and is driven by the opposing selective pressures of the antiretroviral agents themselves versus the decreased fitness conferred by the mutation. Combination therapy is more successful than monotherapy because virus with multiple preexisting mutations is more rare than virus with single or double mutations, which is common. Though such multiple mutants may arise, they may be much less stable, because they are less fit and subject to much greater counterselection. Thus, the strategies for antiretroviral therapy should be:
Dr. Giuseppe Pantaleo, from the University of Lausanne in Switzerland, discussed HIV pathogenesis from an immunologic approach. He focused on the initial immune response to acute HIV infection and suggested that prognosis may be highly correlated with this response.
The components of the immune response to HIV infection include the cytotoxic T-lymphocyte (CTL) response, the cytokine/chemokine response, and the humoral (antibody) response. Most of Dr. Pantaleo's talk focused on the CTL response and its importance in determining the outcome of HIV infection.
The CTL response is heralded by large expansions of CD8 cells during the first few weeks of infection. The diversity of that expansion appears to correlate with clinical outcome, so that those who respond with a restricted repertoire (one to "a few" CD8 clones) may progress more rapidly because of the higher probability of "viral escape" from the immune response, while those with multiple clones will have greater downregulation of HIV replication and will progress more slowly, a situation somewhat analogous to monotherapy versus combination therapy.
Thus, Dr. Pantaleo proposed that in addition to a so-called "virologic" set point, occurring approximately 6 months after the acute retroviral syndrome, there is also an immunologic setpoint, occurring at approximately 4 weeks. The CD8 cell repertoire at that point may have considerable prognostic implications. For those who have lost CD8 clones during primary infection, true immune restoration may not be possible. With time there are mechanisms that can further weaken the cellular immune response to HIV, including selective pressure favoring viral escape mutants (again, analogous to antiretroviral resistance) as well as deletion of CD8 cytotoxic T-cell clones.
Dr. Pantaleo concluded with a discussion of the implications of his model: that antiretroviral therapy should be started as soon as possible during primary infection, or during the first year after infection; that the effectiveness of antiretroviral therapy may diminish as it is delayed; and that we shouldn't rule out combining antiretroviral therapy with interventions to strengthen the immune response.
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