Map

HIV Pathogenesis and HIV Reservoirs: Our group’s principal areas of research interest focus on molecular and medical virology and the application of innovative techniques and assays which provide new insights into disease pathogenesis and treatment, especially for HIV. Our current work focuses on understanding the genetic characteristics and dynamics of persistent HIV across a range of tissues and cells to guide and assess treatment interventions designed to reduce persistent HIV reservoirs and inform HIV eradication strategies.

COURSES TAUGHT

Infection: Causes and Defense: preclinical lectures for medical students

Antiviral Therapy Seminars: preclinical seminars for medical students

New Insights into the Host-HIV Relationship: graduate student lecture series

Virology and Antiviral Therapy: undergraduate students in biomedical technology

DARE: Delaney AIDS Research Enterprise to find a cure: Our research group is a part of an ongoing international initiative concerned with HIV eradication strategies funded by the US NIH

Characterizing Latent HIV-1 Reservoirs: Our research group is conducting an in-depth analysis of peripheral blood and tissue samples from patients to provide an unprecedented systematic survey of three important factors which influence the magnitude and nature of the HIV reservoir in patients on effective therapy: treatment initiation (during acute versus chronic infection); the pool of follicular dendritic cell-associated virions in lymphoid follicles; and host genetics (CCR-5 Δ32 heterozygosity).

Genetic analysis of unspliced HIV RNA produced during HDAC inhibitor therapy: Despite advances in the treatment of HIV-infected patients, including the complete or near-complete inhibition of viral replication with standard therapies, replication-competent HIV persists indefinitely in all infected individuals. This latent form persists even in persons under effective therapy and can actively and life-threateningly rebound if therapy stops or is taken incorrectly. One promising approach to eradicate HIV and cure infected individuals is to reactivate and target this latent HIV for elimination. During recent clinical trials, latent HIV was reactivated in patients who while on effective therapy were also treated with compounds called histone deacetylaseinhibitors. In conducting this study we are investigating the genetic makeup of this reactivated HIV to determine which cells and tissue compartments are producing this HIV. We anticipate this study will reveal which cells are most prone to HIV reactivation by histone deacetylaseinhibitor therapy. In addition, this study will provide evidence that this reactivated HIV is an important prognostic marker for the latent form of HIV found in cells, an important step in current treatment strategies aimed at eradicating and curing HIV infection.

Longitudinal assessment of the relationship between immune activation and HIV persistence: T cell proliferation, differentiation and activation have poorly defined effects on the latent HIV reservoir during ART. We recently found that the most consistent association correlate of reservoir size is the frequency of memory CD4+ T cells expressing HLA-DR, which is upregulated upon activation. In conducting this project we are measuring the levels of cellular activation markers over time in subjects who have been on ART for 15 years, and determining how these markers predict changes of infection frequency, genetic makeup, and replication competency of HIV in memory T cells. Specifically, we will determine if the inducible reservoir is enriched in cells expressing markers of activation.

By Randy Dotinga
HealthDay Reporter

TUESDAY, Nov. 26, 2013 (HealthDay News) -- A new study suggests that the replication of HIV may slow or stop altogether in patients who are on long-term treatment, although remnants can still lurk in the body.

And the researchers now suspect that the virus is especially weak in those people who started treatment immediately after becoming infected.

The study is very small, involving just eight patients. However, the findings add more evidence to the debate over how soon patients should begin drug treatment after they're diagnosed as being infected with HIV. One of the study authors is ready to say that treatment must begin immediately.

"Patients should be started on therapy as soon as they are diagnosed to prevent the virus from hiding in large numbers of cells," said the researcher, Sarah Palmer, deputy director of the Center for Virus Research at Westmead Millennium Institute for Medical Research, in Australia. "Diagnosing HIV infection early and initiating therapy immediately is crucial for limiting the number of cells containing HIV."

While doctors can use drugs to kill the AIDS virus in the body, it's impossible to eliminate it completely. That means there's no cure for HIV infection or AIDS, the potentially deadly condition that the virus causes.

But what does the virus do when a patient is on medication -- does it keep replicating [making copies of itself] or does it hide? The authors of the new study sought to find an answer by analyzing immune-system cells taken from eight HIV-infected patients. All had been taking anti-HIV drug treatment for years.

This combined drug treatment is known as antiretroviral therapy (ART).

The researchers analyzed the cells and found that drug treatment appeared to stop the virus from replicating -- an important finding that suggests a possible weakness. However, HIV didn't vanish but instead hid in certain types of immune-system cells known as "resting memory T cells." These cells "remember" how to fight a particular body invader, such as a germ or virus and sit around waiting for it to return.

"These cells can remain dormant for many years even though they are carrying HIV," Palmer said. "When these cells start to replicate or are stimulated to replicate as part of our normal immune response, they also produce HIV, keeping the virus viable. Essentially, these cells are a ticking time bomb in patients, and once they are ignited they explosively produce HIV."

This finding confirms previous research showing that the lurking virus is "very stable for years," said David Schaffer, director of the Berkeley Stem Cell Center at the University of California, Berkeley. "It means that treatments must be developed to directly eliminate this long-lived pool, which is challenging," said Schaffer, who is familiar with the study's findings.

However, there's some good news. The numbers of these cells were smaller in patients who had started treatment soon after being diagnosed instead of waiting until they began to show symptoms.

"Diagnosing HIV infection early and initiating therapy immediately is crucial for limiting the number of cells containing HIV," Palmer said. "The scientific community must develop better strategies to flush HIV from its hiding place in patients without causing new infections."

Schaffer agreed. A treatment can't just halt the virus from growing in the body and wait for the infected cells -- the "latent pool" -- to die out, he said. "Finding a cure for HIV means that therapies must be developed to directly eliminate the latent pool of virus."

The study will appear online in this week's issue of the Proceedings of the National Academy of Sciences.