During the past year, scientists have shown that HIV persists in a latent form within a relatively small number of resting CD4+ T cells, even in patients who have received prolonge combination antiretroviral therapy and have no readily detectable virus in their blood. Latently infected CD4+ T cells are potential sources of new viral replication if a patient stops therapy, and pose a formidable obstacle to the goal of eradicating HIV from a person's body, particularly if drug resistance develops.
New data show that latent pools of infected cells are established very early in the course of HIV infection, even if a patient is treated expeditiously with highly active antiretroviral therapy ("HAART" -generally a three- or four-drug combination that includes a protease inhibitor). Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID) and chief of the NIAID Laboratory of Immunoregulation (LIR), will present these and other new findings at the 12th World AIDS Conference in Geneva, Switzerland.
We have shown that initiating HAART as soon as 10 days after the onset of the symptoms of acute HIV infection does not prevent the formation of a latent reservoir of virus," says Dr. Fauci. "By the time high levels of HIV are detectable in the blood, the virus probably has spread to the lymphoid organs and established a pool of latently infected cells. "Our group and others are pursuing studies to identify and treat people recently exposed to HIV,before the burst of virus replication, which occurs in most patients soon after infection. Such studies will help determine whether it will be possible to prevent the early establishment of latent pools of HIV."
In Geneva, Dr. Fauci also will discuss the potential for diminishing latent pools of HIV - the possibility of "flushing out" the virus (at least in the test tube) - by stimulating latently infected CD4+ T cells with antibodies to the CD3 molecule on the cell surface, or with combinations of cytokines such as interleukin-2 (IL-2), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha).
This approach to purging the HIV from latently infected cells assumes that cells activated to release virus will spontaneously die, and the released virus will be prevented from spreading to other cells because of the HAART that the patients are receiving," Dr. Fauci says. "In our in vitro studies, we have shown that it is indeed possible to decrease the number of latently infected cells, but a single round of purging does not completely eliminate the virus. "Further in vitro studies, as well as clinical trials with HIV-infected patients, will help determine the feasibility of completely eliminating the latent reservoir of HIV-infected cells by repeated, intermittent exposure to activation signals in the setting of HAART," he says.
Dr. Fauci notes that numerous factors are involved in the initiation of HIV infection, in determining levels of viral replication in people infected with HIV, and ultimately, in the rate of disease progression among HIV-infected individuals. Among these are factors intrinsic to the infected individual (the "host"), notably the network of immune signaling molecules (especially cytokines and CC-chemokines) involved in the normal immune response.
Pro-inflammatory" cytokines such as IL-2, IL-6 and TNF-alpha, boost replication of certain strains of HIV. CC-chemokines such as RANTES, MIP-1alpha and MIP1-beta, can have either a positive or negative effect on HIV replication, depending on the strain of the virus. "The emerging picture of HIV pathogenesis is one of a "delicate balance" between factors that drive viral replication and those that inhibit the virus," says Dr. Fauci. When an HIV-infected patient Is taking HAART, pro-inflammatory cytokines and other factors which can boost HIV production are still present in their lymph nodes and related organs. However, the powerful effects of HAART can reduce viral replication dramatically, sometimes to the point where HIV can be found only in a latent form within the genes of resting CD4+ T cells. Dr. Fauci and colleagues have shown in vitro that when HAART is withdrawn, the effects of HIV-inducing cytokines and other factors once again promote the active production of virus.
We feel that these data provide a mechanistic explanation for the clinical phenomenon of rapid viral "rebound" in many patients with low or undetectable levels of virus in their bloodstream who discontinue HAART. When a patient stops taking HAART because of toxicity or other reasons, or if HIV becomes resistant to the drugs, the virus almost inevitably comes roaring back because latently infected cells are awash in stimulatory factors in the normal environment of the lymph nodes," says Dr. Fauci. "These data underscore the need to develop comprehensive treatment strategies that not only block HIV replication but also modulate the host factors that drive such replication."
The lead investigators in the NIAID studies to be discussed are Drs. Fauci and Tae-Wook Chun of the LIR. Collaborators include Delphine Engel of the LIR, and Drs. Lawrence Corey and M. Michelle Berrey, and Theresa Shea of the University of Washington in Seattle.
Press reases, fact sheets and other NIAID-related material are Available on the internet via the NIAID home page at http://www.niaid.nih.gov. The home page for the 12th World AIDS Conference is http://www.aids98.ch.