Fauci to Present New Insights into HIV Latency at 12th World AIDS Conference

National Institute of Allergy and, Infectious DiseasesEMBARGOED FOR RELEASE, Tuesday, June 30, 1998, 3:00 AM Eastern Time, Greg Folkers, gfolkers@nih.gov

During the past year, scientists have shown that HIV persists in alatent form within a relatively small number of resting CD4+ T cells,even in patients who have received prolonged combination antiretroviraltherapy and have no readily detectable virus in their blood. Latentlyinfected CD4+ T cells are potential sources of new viral replication ifa patient stops therapy, and pose a formidable obstacle to the goal oferadicating HIV from a person's body, particularly if drug resistancedevelops.

New data show that latent pools of infected cells are established veryearly in the course of HIV infection, even if a patient is treatedexpeditiously with highly active antiretroviral therapy ("HAART" -generally a three- or four-drug combination that includes a proteaseinhibitor). Anthony S. Fauci, M.D., director of the National Instituteof Allergy and Infectious Diseases (NIAID) and chief of the NIAIDLaboratory of Immunoregulation (LIR), will present these and other newfindings at the 12th World AIDS Conference in Geneva, Switzerland.

"We have shown that initiating HAART as soon as 10 days after the onsetof the symptoms of acute HIV infection does not prevent the formation ofa latent reservoir of virus," says Dr. Fauci. "By the time high levelsof HIV are detectable in the blood, the virus probably has spread to thelymphoid organs and established a pool of latently infected cells.

"Our group and others are pursuing studies to identify and treat peoplerecently exposed to HIV, before the burst of virus replication, whichoccurs in most patients soon after infection. Such studies will helpdetermine whether it will be possible to prevent the early establishmentof latent pools of HIV."

In Geneva, Dr. Fauci also will discuss the potential for diminishinglatent pools of HIV - the possibility of "flushing out" the virus (atleast in the test tube) - by stimulating latently infected CD4+ T cellswith antibodies to the CD3 molecule on the cell surface, or withcombinations 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 assumesthat cells activated to release virus will spontaneously die, and thereleased virus will be prevented from spreading to other cells becauseof the HAART that the patients are receiving," Dr. Fauci says. "In ourin vitro studies, we have shown that it is indeed possible to decreasethe number of latently infected cells, but a single round of purgingdoes not completely eliminate the virus.

"Further in vitro studies, as well as clinical trials with HIV-infectedpatients, will help determine the feasibility of completely eliminatingthe latent reservoir of HIV-infected cells by repeated, intermittentexposure to activation signals in the setting of HAART," he says.

Dr. Fauci notes that numerous factors are involved in the initiation ofHIV infection, in determining levels of viral replication in peopleinfected with HIV, and ultimately, in the rate of disease progressionamong HIV-infected individuals. Among these are factors intrinsic tothe infected individual (the "host"), notably the network of immunesignalling molecules (especially cytokines and CC-chemokines) involvedin the normal immune response.

"Pro-inflammatory" cytokines such as IL-2, IL-6 and TNF-alpha, boostreplication of certain strains of HIV. CC-chemokines such as RANTES,MIP-1alpha and MIP1-beta, can have either a positive or negative effecton HIV replication, depending on the strain of the virus. "The emergingpicture of HIV pathogenesis is one of a 'delicate balance' betweenfactors that drive viral replication and those that inhibit the virus,"says Dr. Fauci.

When an HIV-infected patient is taking HAART, pro-inflammatory cytokinesand other factors which can boost HIV production are still present intheir lymph nodes and related organs. However, the powerful effects ofHAART can reduce viral replication dramatically, sometimes to the pointwhere HIV can be found only in a latent form within the genes of restingCD4+ T cells. Dr. Fauci and colleagues have shown in vitro that whenHAART is withdrawn, the effects of HIV-inducing cytokines and otherfactors once again promote the active production of virus.

"We feel that these data provide a mechanistic explanation for theclinical phenomenon of rapid viral 'rebound' in many patients with lowor undetectable levels of virus in their bloodstream who discontinueHAART. When a patient stops taking HAART because of toxicity or otherreasons, or if HIV becomes resistant to the drugs, the virus almostinevitably comes roaring back because latently infected cells are awashin stimulatory factors in the normal environment of the lymph nodes,"says Dr. Fauci.

"These data underscore the need to develop comprehensive treatmentstrategies that not only block HIV replication but also modulate thehost 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 DelphineEngel of the LIR, and Drs. Lawrence Corey and M. Michelle Berrey, andTheresa Shea of the University of Washington in Seattle.

NIAID is a component of the National Institutes of Health (NIH). NIAIDconducts and supports research to prevent, diagnose and treat illnessessuch as HIV disease and other sexually transmitted diseases,tuberculosis, malaria, asthma and allergies. NIH is an agency of theU.S. Department of Health and Human Services.