PROGRESSION
The Gastrointestinal Tract in HIV-1 Infection: Questions, Answers, and More Questions!
The GI tract is targeted during all stages of HIV disease, and this is especially so during acute and early HIV infection. CD4 cells are preferentially lost from the GI tract within weeks of HIV infection. Despite long-term antiretroviral therapy, CD4+T-cell reconstitution remains deficient in the GI tract in spite of the reconstitution seen in the peripheral blood.
Acute HIV Infection: Recent Issues in Treatment, Progression, and Superinfection
Long-term outcome studies of persons enrolled early in the course of HIV infection continue to yield important data regarding transmission dynamics, disease progression, efficacy of treatment, and incidence and consequence of superinfection. The Options Project at San Francisco General Hospital is such a study, and Dr. Frederick Hecht, a co-director of the program, and his colleagues continue to make headway in exploring various pathogenesis- and treatment-related issues affecting newly infected patients. In this article, Dr. Hecht returned to PRN to provide members with an update on treatment and treatment interruptions in early HIV infection, the role of T-cell activation in acute HIV infection, and the effect of sequential superinfection with variants of HIV.
Tracing the Origin of the AIDS Pandemic
For those lucky enough to be in attendance, the keynote lecture delivered at the 6th Conference on Retroviruses and Opportunistic Infections (CROI) was nothing short of a jaw-dropping experience. Dr. Beatrice Hahn of the University of Alabama at Birmingham presented the first concrete evidence of the primate origin of HIV-1, the much more prevalent of the HIV types responsible for the AIDS pandemic. The official report of her team’s findings, published in a February 1999 issue of Science, was a no less captivating example of seminal scientific research (Gao, 1999). The following article summarizes Dr. Hahn's presentation to the Physicians' research network on this fascinating topic.
Making Sense of HIV Pathogenesis
In the acute phase of infection, there is massive loss of memory CD4+ cells. And in the chronic phase of infection, there is significant immune activation. In this presentation to The Physicians' Research Network, Dr Douek argues that we have to rethink our idea of HIV pathogenesis. We’ve always thought of it as a slow depletion from the acute phase through the chronic phase, over a period of approximately ten years. However, we now know that HIV is truly a rapid disease. Within three weeks after infection, you’ve lost most of the CD4+ cells in your body.
Women and HIV: An Overview
The care of HIV-infected women is an evolving process. Research continues to define the ways in which HIV-infected men and women are similar and different, findings that will continue to shape—and reshape—the standards of care that apply to both sexes. In her presentation to the Physicians’ Research Network, Dr. Judith Aberg stressed that efforts are needed to expand prevention efforts and to increase availability of testing to at-risk women. “We still have too many women presenting late in the course of infection,” she said. “The research showing that women do not progress faster than men is important. Now we need to start making sure that women aren’t allowed to progress because of limited access to testing and services. Fear, isolation, and lack of information remain key issues to address.”
Novel Viral Markers Predict HIV Disease Progression
Over the past 20-plus years of the AIDS epidemic, clinicians have come to appreciate that while there are relatively predictable markers of HIV disease progression—viral load and CD4+ cell counts being the most widely utilized—the course of HIV infection is extremely variable among individuals. Building upon these observations, researchers have been determined to unlock the mysteries of the elusive host, immunologic and virologic factors—and biological markers—associated with HIV disease progression.
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HIV Long-Term Nonprogression: Insights into Pathogenesis and Viral Control
After an individual in infected with the virus, progression to AIDS—provided that antiretroviral therapy is not used—typically occurs within ten years. However, for a small group of individuals, HIV infection runs an unusually benign course. These patients, dubbed long-term nonprogressors (LTNPs), maintain very low viral loads and stable CD4+ cell counts for many years—indefinitely in some cases—without the assistance of antiretroviral therapy. Understanding the factors that contribute to long-term nonprogression will hopefully yield greater insights into the pathogenesis of HIV infection and will be crucial for vaccine design and the development of therapeutic modalities.
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Mechanisms of T-Cell Depletion and Regeneration in HIV Disease
More than 20 years since the beginning of the AIDS epidemic, there is still no clear-cut explanation for HIV's most basic and insidious effect in the human body: the gradual depletion of CD4+ T-lymphocytes in the absence of antiretroviral treatment. At the same time, there is little consensus regarding the mechanism(s) by which CD4+ cell counts improve once therapy is commenced. On some level, the fact that CD4+ cell counts do improve-both quantitatively and qualitatively-with antiretroviral therapy should be enough to satisfy the hearts and minds of HIV-treating clinicians. But there is much to be gained medicinally with the continued exploration of these fundamental questions. For example, antiretroviral therapy plays a critical role in halting the accelerated destruction of CD4+ cells, perhaps the most widely accepted mechanism of HIV-associated CD4+ cell depletion. But there is also at least one other mechanism to ponder-the impaired production of new CD4+ cells as a result of HIV infection-that may have significant bearing on the evaluation and potential use of various immune-based therapies in the clinical management of HIV-positive patients.
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Update on IL-2: Where It's Been and Where It's Going
Perhaps no other drug in the history of HIV/AIDS treatment research has been more extensively studied than recombinant interleukin-2 (IL-2). It has been evaluated in numerous proof-of-concept and phase II clinical trials—both alone and in combination with antiretrovirals or with other immune-based therapies—involving a broad spectrum of patients, including those in the acute, chronic, and late stages of HIV disease. Ironically, however, it still lacks a licensed therapeutic indication in HIV. This may change sometime during the next few years. Massive phase III clinical trials are now under way to address fundamental questions regarding the clinical utility of IL-2 treatment. These results—along with other data from pivotal IL-2 clinical trials—will be reviewed by the U.S. Food and Drug Administration and may help carve out a niche for the drug in the standard-of-care for HIV-positive people.
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The Road to Eradication: Is HAART Hard Enough?
At the ground-breaking 1996 International AIDS Conference, Markowitz and Ho, postulated 1.5--3 years of “maximally suppressive” antiretroviral therapy might eradicate HIV infection. Since then, research has shown that HAART may not completely shut down HIV replication, and that infection may persist in reservoirs. “But this does not mean that we should abandon concepts of eradication or remission,” stated Dr Markowitz at a meeting of PRN in NYC, “the shortcomings that we see today, especially the emergence of drug resistance, might be less of a concern if we can maximize the benefits of therapies that are now available, as well as those in development.”
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