CD4 T Cells From "Elite Controllers" Resist Infection by HIV

Daniel M. Keller, PhD

October 22, 2010

October 22, 2010 (Vancouver, BC) — Elite controllers, the very small proportion of HIV-infected individuals who, without treatment, have undetectable viral levels, have CD4 T cells that resist infection with the virus. Their CD4 cells have a 10- to 100-fold higher expression of p21, a host protein originally described as a product of a tumor suppressor gene. Experiments show that modulating the intracellular level of p21 affects the level of HIV replication in the cell.

Dr. Mattias Lichterfeld, right, and Dr. Joel Gallant
(Photo by Jeff Vinnick)

Speaking here at the Infectious Diseases Society of America 48th Annual Meeting, Mathias Lichterfeld, MD, PhD, from the Infectious Diseases Division at Massachusetts General Hospital, and instructor in medicine at Harvard Medical School in Boston, said his research study focused on the steps in HIV replication in CD4 T cells from elite controllers (n = 15), from HIV-1 negative individuals (n = 14), from individuals with progressive HIV-1 disease (n = 16), and from infected patients treated with highly active antiretroviral therapy (HAART) (n = 10). The cells were analyzed after ex vivo infection with an HIV-1 viral vector or primary isolates to quantify extra- and intrachromosomal HIV-1 DNA and messenger (m)RNA. Expression of the p21 gene was quantified in quiescent and activated CD4 T cells from elite controllers and from the reference populations.

CD4 T cells are the primary target cells for HIV, and Dr. Lichterfeld reported that these cells from elite controllers were significantly less susceptible to infection with HIV-1 than cells from the reference populations (< .01). Cells from elite controllers showed less effective reverse transcription of viral RNA to DNA and of viral mRNA transcription from proviral DNA. According to an abstract describing the work, in laboratory experiments, the less efficient viral replication in the cells of elite controllers was associated with a 10- to 20-fold higher expression of p21 than in the cells of the reference populations (< .001). Using an ex vivo HIV-1 infection assay, Dr. Lichterfeld showed that chemical blockade of p21 enhanced reverse transcription and viral mRNA transcription in CD4 cells (= .01).

He said the data indicate that upregulation of p21 likely accounts for the relative resistance of CD4 cells from elite controllers to HIV-1 infection, and allows these individuals to maintain generally undetectable viral loads without receiving HAART. "It's not a complete resistance. They still can be infected, but the susceptibility is [very] reduced," Dr. Lichterfeld noted. In elite controllers, p21 "is about 10- to 100-fold higher . . . than in other patients."

A number of different centers have shown that T cell responses against HIV in elite controllers are very strong, and that they are very effective in resisting HIV, he said. "So once you have a CD4 cell system that's less susceptible to HIV, you might be able to build a better T cell response and you might be able to build a better antibody response. All these things might be working together to provide a very powerful way of restricting HIV."

He said the best estimates are that elite controllers make up about 0.3% to 1.0% of all HIV-infected individuals. Their CD4 counts are generally comparable to uninfected individuals. Possibly about 5% of elite controllers eventually develop declining CD4 counts and require anti-HIV treatment.

Because p21 acts within CD4 cells, it is probably not be feasible to develop such a molecule for administration to a person. But Dr. Lichterfeld said his findings "would potentially offer an alternative way of enhancing resistance to HIV in a broader patient population if we were able to manipulate this protein in one way or another."

Joel Gallant, MD, professor of medicine and epidemiology in the Division of Infectious Disease at Johns Hopkins University School of Medicine in Baltimore, Maryland, said that these patients might not be completely normal, because "some data suggest that elite controllers still have higher levels of inflammation and immune activation than people who are on antiretroviral therapy with the same viral loads." He said that occasionally elite controllers progress with declining CD4 counts, "so there are at least some suggestions that even an elite controller could potentially benefit from therapy, but it would be very hard to prove that clinically, because these people tend to do well, and bad things don't happen to them." Therefore, most of the people with normal CD4 counts are followed with just observation.

Dr. Lichterfeld has disclosed no relevant financial relationships. Dr. Gallant reports receiving grant support and consulting fees from Gilead Sciences; receiving consulting fees from Abbott Laboratories; and being a scientific advisor to Bristol-Myers Squibb, Merck, Sangamo BioSciences, and Tibotec.

Infectious Diseases Society of America (IDSA) 48th Annual Meeting: Abstract 88. Presented October 22, 2010.


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