Broad-Spectrum Killer T-Cells May Be Needed to Fight Latent HIV

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Cytotoxic T-cells with a wide spectrum of activity may be necessary to detect and destroy memory CD4 T-cells containing inactive reservoir HIV from people who start antiretroviral therapy (ART) during chronic infection, according to research reported in the January 7 edition of Nature. People who start treatment very early, however, may still have non-mutated virus that is susceptible to detection by normal killer T-cells -- and a therapeutic vaccine may help boost immune responses in those treated later.

From the time of initial infection HIV inserts its genetic material into resting CD4 T-cells, creating a persistent reservoir. This inactive HIV is not recognized by the immune system and is not sensitive to antiretroviral drugs. But when resting CD4 cells become active, the virus can start to replicate and rekindle infection, which is why most people must remain on life-long ART. One approach to curing HIV involves reactivating latent CD4 cells and releasing their HIV, but it is not clear whether typical immune mechanisms would eliminate these newly awakened cells.

Kai Deng and Robert Siliciano from Johns Hopkins University and colleagues from Yale, University of California at San Francisco, and Regeron Pharmaceuticals extracted immune cells and reservoir-based HIV from 25 people, 10 of whom started combination ART early (within 3 months of infection) and 15 of whom started later. The cells and virus were examined in the laboratory and in a mouse model.

Most HIV-infected resting CD4 cells from the early-treated participants were detectable by cytotoxic T-lymphocytes (CTLs), or killer T-cells, while nearly all HIV in resting cells from patients treated later had mutations that allow them to evade detection. However, stimulating killer T-cells with HIV protein fragments enabled them to recognize and eliminate CD4 cells containing mutated reservoir virus.

"The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication," the study authors concluded. "Our results demonstrate that chronically infected patients retain a broad-spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir."

"[U]nderstanding barriers to cure and defining the biology underlying these barriers are the first steps towards overcoming this viral enemy," Louis Picker of the Vaccine and Gene Therapy Institute at Oregon Health and Science University and Jeffrey Lifson of the AIDS and Cancer Virus Program at Frederick National Laboratory wrote in an accompanying editorial. "HIV cure will almost certainly require a multimodal therapeutic approach incorporating both pharmacological activation of latent reservoirs and immune-mediated clearance mechanisms, with each component designed to exploit one of this formidable enemy's few weaknesses."

Below is an edited excerpt from a Yale news release describing the research and its findings in more detail.

Broad Immune Response May Be Needed to Destroy Latent HIV

January 7, 2015-- Ziba Kashef, Yale News -- A major barrier to finding a cure for HIV/AIDS is the presence of latent HIV in the cells of chronically infected individuals. But a team of Yale and Johns Hopkins researchers may have pinpointed a strategy for eliminating the residual virus.

The study is published online on Jan. 7 by the journal Nature.

Despite treatment with antiretroviral therapy, HIV persists in patients in a latent reservoir. Yale researchers and their co-authors at Johns Hopkins University, the University of California-San Francisco, and Regeneron Pharmaceuticals explored the question of whether specific immune cells known as killer T cells, or CTLs, could be stimulated to effectively target and destroy infected cells that harbor dormant viruses. The results of this study have major implications for the design and development of a therapeutic vaccine to cure HIV patients, said the researchers.

In their investigation, the researchers first studied the viral DNA of two groups of 25 HIV patients, including 10 who had started antiviral therapy within first three months of infection and 15 who had already been chronically infected before receiving therapy. They found that the viral reservoirs of chronically infected individuals were dominated by "escape mutations," or variants that allow HIV to evade detection by CTLs.

"These results help explain why none of the current vaccines can clear HIV from the body," said Liang Shan, a postdoctoral fellow at Yale School of Medicine and co-senior author of the paper. "The next question was how, given a boost, CTLs could recognize and kill infected cells despite the escape mutations."

Led by Dr. Robert Siliciano, co-senior author and professor of medicine at Johns Hopkins University, the researchers addressed this question by exposing CTLs isolated from patients to mixed pieces of HIV proteins and then observing their function in vitro. They found that with this stimulation, the CTLs could provide a more broad and effective immune response that targeted unmutated portions of HIV proteins. Residual HIV from both groups of patients could be targeted by the newly stimulated CTLs.

"The next big thing was to test this strategy outside the petri dishes," said co-senior author Richard Flavell, chair and Sterling Professor of Immunobiology at Yale School of Medicine. To that end, the researchers also conducted a small-scale preclinical trial using "humanized" mice carrying HIV-patient immune system. In the vaccine group, the stimulated CTLS that targeted unmutated HIV epitopes were able to control the infection, and in some mice, they cleared the circulating virus. In the placebo group, HIV infection rapidly progressed in the mice.

"Our study suggests that directing CTL responses to unaltered pieces of virus may be the future direction for the development of therapeutic vaccine to clear HIV," said Shan.

Flavell added, "Another important implication coming from this study is that it shows the great value of reconstructing a patient immune system in mice in the studies of a disease, such as infection or cancer, and suggests how this can be of value in the development of medicines."

1/21/15

References

K Deng, M Pertea, A Rongvaux, R Siliciano, et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517:381-385. January 15, 2015.

LJ Picker and JD Lifson. HIV: Seeking ultimate victory (editorial). Nature 517:281-282. January 15, 2015.

Other Sources

NIAID. NIAID Grantees Overcome Hurdle to Kill HIV-Infected Cells Brought out of Hiding. NIH News press release. January 7, 2015.

Z Kashef. Broad Immune Response May Be Needed to Destroy Latent HIV. Yale News press release. January 7, 2015.