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
There is still considerable controversy over appropriate clinical management strategies for patients diagnosed with HIV during acute or early stage infection. However, it is widely accepted that enrolling longitudinal cohorts to study such patients is vital. Long-term outcome studies of persons enrolled early in the course of injection continue to yield important data regarding transmission dynamics, disease progression, efficacy of treatment, and incidence and consequence of superinfection. Not only are these studies helping to determine how best to clinically manage patients diagnosed early in the course of HIV disease, they are contributing significantly to the research exploring virologic, immunologic, and treatment questions in patients with chronic infection.
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) at the end of January 1999 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).
Making Sense of HIV Pathogenesis
The first question to ask in attempting to understand the pathogenesis of HIV infection is not how the virus causes disease, but why. “In its natural host,” Dr. Daniel Douek stated, “HIV does not cause disease. SIV in old-world monkeys and chimpanzees in Africa does not cause disease. These animals have very high viral loads, but none of them progress to AIDS. So why does the same virus, when you put it into humans, cause disease at all? No other infection in humans, whether it’s acute or chronic, causes such a profound and inevitable depletion of CD4+ cells.”
Women and HIV
As is true with virtually every aspect of the medical management of HIV infection, 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.
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. “Everyone is familiar with the graph showing peak in viremia and then the virologic set point that’s achieved, followed by a progressive decline in CD4+ cells and the development of symptoms, usually in about eight to ten years after the point of infection,” Dr. Eric Daar explained. “But there’s a lot of heterogeneity among individuals in this regard. There are some individuals who have high viral set points, with their CD4+ cells declining more quickly, some even progressing to AIDS within the first 12 to 24 months. At the other end of the spectrum are the unusual long-term nonprogressors, who maintain viral suppression, high CD4+ cell counts, and remain completely asymptomatic for many years. And in between, we see varying rates of disease progression.”
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HIV Long-Term Nonprogression: Insights into Pathogenesis and Viral Control
When it comes to the natural history of HIV infection, very few generalizations can be made. After an individual in infected with the virus, progression to AIDS—provided that antiretroviral therapy is not used—typically occurs within ten years. “This basically depends on the steady-state viral load,” explained Dr. Marylyn Addo. “Patients who maintain a high viral load after infection has been established are likely to develop AIDS faster than those with lower viral loads.” 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. And it is these LTNPs that have been the intense focus of several research teams around the world. 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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