Better Dendritic Cell Recognition May Explain Stronger Response to HIV in Elite Controllers

Dendritic cells -- the first line of immune defense-- may be better able to recognize HIV in elite controllers, triggering greater cytokine production and interferon-stimulated gene expression, which ultimately results in more effective HIV-specific T-cell responses, according to research reported in the June 11 edition of PLoS Pathogens. Better understanding of this process may be helpful in the search for a functional cure, by improving T-cell immunity against HIV in people who are not natural controllers.

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Broadly Neutralizing Antibodies May Prevent Reservoir HIV from Entering T-Cells

HIV-specific broadly neutralizing antibodies may be able to prevent virus emerging from latent reservoir sites from entering CD4 T-cells, as well as suppressing viral replication if HIV does manage to get in, according to NIAID research published in the August 25 advance edition of Proceedings of the National Academy of Sciences.

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Long-time Researcher Discusses Myths About HIV Pathogenesis, Treatment, and Cure

Over the 3 decades of the epidemic a number of misconceptions have arisen about HIV infection, how the immune system fights the virus, and how best to treat and potentially cure it, along with a number of important questions that remain unanswered, according to an opinion article in the April 13 advance edition of Trends in Molecular Medicine by Jay Levy from the University of California at San Francisco, one of the first researchers to study HIV. The trend toward earlier antiretroviral therapy and treatment-as-prevention are among the issues he contests.

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Gut Microorganisms May Play a Role in HIV Response

Antibodies in people with HIV that target the virus's gp41 envelope protein can cross-react with normal intestinal bacteria, helping to explain why these antibodies are not effective in controlling HIV infection, according to research published in the August 13 edition of Cell Host & Microbe.

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Valacyclovir May Reduce HIV Viral Load Even in People Without Herpes

The antiviral drug valacyclovir (Valtrex and generics), used to treat herpes simplex virus type 2 (HSV), led to a decrease in HIV viral load even among individuals who did not have genital herpes, according to a small study reported in the March 3 advance edition of Clinical Infectious Diseases.

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Kidney Drug Sevelamer May Reduce Gut Leakage During Acute HIV Infection

The phosphate-binding agent sevelamer can bind to bacterial toxins and reduce excessive immune activation in macaque monkeys with a simian virus similar to HIV, according to a report in the June 2 Journal of Clinical Investigation. A related study, however, failed to see a reduction in inflammation biomarkers in people with untreated HIV disease.

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Elite Controllers Have Higher Hospitalization Rate, HIV May Hide in B-Cells

Elite controllers -- people who naturally maintain viral suppressed without antiretroviral treatment -- had higher rates of hospitalization than people with HIV on antiretroviral therapy, most commonly for cardiovascular conditions, researchers reported in the December 15 Journal of Infectious Diseases. A related study showed that B cell follicles may act as a reservoir for an HIV-like virus in elite controller monkeys.

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Coral Proteins Block HIV from Entering Cells, May Be Useful in Microbicides

A set of proteins derived from soft coral identified from a National Cancer Institute repository of biological chemicals can bind to HIV and prevent it entering immune cells, suggesting it may have potential for use in microbicide gels or other products to prevent transmission of the virus, according to a poster presented at the Experimental Biology 2014 meeting last week in San Diego.

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

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.

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Inherited Low Cholesterol in Immune Cells Linked to Slower HIV Disease Progression

A genetic variation linked to lower levels of intracellular cholesterol is associated with reduced transmission of HIV between immune cells, which may contribute to slower evolution of disease in non-progressors, according to a report in the April 29, 2014, edition of the electronic journal mBio, published by the American Society for Microbiology.

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HIV Has Become More Virulent Over Time, Not Less, European Study Finds

The largest cohort study ever to look at CD4 count and viral loads in HIV positive people around the time of diagnosis has found evidence that HIV -- at least in Europe -- has become more virulent over time. The average time taken to reach a CD4 count below 350 cells/mm³ has halved over the last 25 years, researchers calculate. This conflicts with recently reported findings from Africa suggesting HIV has gotten weaker, suggesting that local conditions may drive viral evolution in opposite directions.

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Neutralizing Antibodies Offer Clues for HIV Vaccine Research

Researchers have identified broadly neutralizing antibodies targeting variable regions of the HIV-1 envelope that controlled superinfection in a South African woman, according to a report in the March 2, 2014, online edition of Nature. Learning more about such antibodies and how they work may aid the development of preventive or therapeutic HIV vaccines.

Although the body produces antibodies in response to HIV infection, in most people the immune system is not able to control the virus. Some individuals, however, do manage to keep HIV in check, offering insight into what must be done to give other people this ability.

At an HIV community cure workshop preceding the Conference on Retroviruses and Opportunistic Infections (CROI 2014) this week in Boston, Romas Gelezunias from Gilead Sciences described several avenues of HIV cure research, including potent and broadly neutralizing monoclonal antibodies derived from HIV patients he dubbed "elite neutralizers."

Below is an edited excerpt from a press release issued by Wits University describing the Nature study in more detail.

New Research on Potent HIV Antibodies

March 3, 2014 -- The discovery of how a KwaZulu-Natal woman’s body responded to her HIV infection by making potent antibodies (called broadly neutralizing antibodies, because they are able to kill multiple strains of HIV from across the world), was reported today by the CAPRISA consortium of AIDS researchers jointly with scientists from the United States.

The study, published in the scientific journal Nature, describes how the research team found and identified these antibodies in her blood and then duplicated them by cloning the antibodies in the laboratory. The cloned antibodies were then used in a series of experiments in the laboratory to elucidate the pathway followed by her immune system to make these potent antibodies.

The South African researchers in the CAPRISA consortium, which includes scientists from Wits University, the National Institute for Communicable Diseases (NICD) in Johannesburg, the University of KwaZulu-Natal and the University of Cape Town, worked jointly with U.S. partners based at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and Columbia University in New York, to conduct this research.

"In this new publication, we have been able to isolate a broadly neutralizing antibody from this CAPRISA volunteer and trace its origins to understand exactly how it arose. This could lead to new HIV vaccine strategies that are able to stimulate the rare precursors of these protective antibodies," says Professor Lynn Morris, from the National Health Laboratory Service in the Wits School of Pathology who leads the research team at the NICD.

Professor Salim S. Abdool Karim, leader of the CAPRISA consortium and President of the Medical Research Council, commented, "The new insights gained from this KwaZulu-Natal woman into immune responses against HIV bring hope for future HIV prevention and treatment strategies. This woman, referred to as CAPRISA 256 (abbreviated to CAP256), is doing well on antiretroviral therapy and continues to attend the CAPRISA clinic regularly."

Just over a year ago, the same team of South African researchers reported in Nature Medicine (also part of the Nature group of journals) on their discovery relating to two other KwaZulu-Natal women, that a shift in the position of one sugar molecule on the surface of the virus led to the development of broadly neutralizing antibodies against HIV.

All HIV infected people respond to HIV by making antibodies. In most patients, these antibodies are not able to kill a wide range of HIV -- this is described as a lack of neutralization breadth. However, in a few infected people, they naturally make antibodies that kill (neutralize) many different kinds of HIV (i.e. they are broadly neutralizing antibodies).

"Broadly neutralizing antibodies have some unusual features," says Dr. Penny Moore, from Wits University and one of the lead South African scientists on the study based at the NICD. "The outer covering (envelope) of HIV has a coating of sugars that prevents antibodies from reaching the surface to neutralize the virus. In this patient, we found that her antibodies had 'long arms', which enabled them to reach through the sugar coat that protects HIV." In this study, the researchers found that these antibodies had 'long arms' right at the outset. "We discovered that some HIV antibodies are born with 'long arms', requiring less time and fewer changes to become effective in killing HIV," says Moore.

The identification and successful cloning of these special antibodies enables the researchers to make sufficiently large quantities for further testing, similar to the way a medicine used to prevent or treat HIV would be tested. "Our goal is to test these antibodies, preferably in combination with other broadly neutralizing antibodies, directly in patients with HIV infection or in patients at risk of getting infected," said Karim. "But this will take some time as the team is currently planning animal studies as a first step.

Broadly neutralizing antibodies have previously been shown to be effective in preventing and treating HIV infection in animals, but this has never before been shown in humans." The future studies on animals and humans are being supported by the Strategic Health Innovation Partnerships, a unit of the South African Medical Research Council, with funding from the Department of Science and Technology.

The Minister of Science and Technology, Mr. Derek Hanekom, commented: "This study highlights the importance of international scientific partnerships and the contributions of South African researchers to world-class medical science. The Department of Science and Technology is delighted to have contributed funds for this research. We are proud of the South African research team who conducted this ground-breaking study and thank the US partners for their collaboration and support."

The Minister of Health, Dr. Aaron Motsoaledi, pointed out: "Since South Africa has the largest burden of HIV infection globally, we are gratified to see South African scientists, under Professor Abdool Karim's leadership, undertake this research to find solutions that will bring an end to AIDS. We are hopeful that this research takes us one step closer to developing an AIDS vaccine."

3/4/14

Reference

NA Doria-Rose, CA Schramm, J Gorman, JR Mascola, et al. Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature. March 2, 2014 (Epub).

Other Sources

Wits University. New Research on Potent HIV Antibodies. Press release. March 3, 2014.

National Institutes of Health. Study of antibody evolution charts course toward HIV vaccine. Press release. March 2, 2014.

Researchers Capture Images of HIV Spike Proteins that Allow Cell Entry

A team of researchers from the National Institutes of Health, Yale University, and Weill Cornell Medical College has found a way to visualize the activity of "spikes" on the surface of the HIV-1 envelope that change structure to enable the virus to enter host cells, according to reports published simultaneously in the October 8 editions of Science and Nature.

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Inflammation Markers Linked to Disease Progression and Death in People with HIV

Levels of several inflammatory biomarkers were associated with a higher risk of developing AIDS-defining and non-AIDS events among participants in a large clinical trial, researchers reported in the February 1, 2014 Journal of Acquired Immune Deficiency Syndromes. A related study also saw a link between inflammatory markers and mortality in a group of HIV positive adults with alcohol problems.

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HIV Superinfection May Boost Viral Load but Does Not Worsen Disease Progression

Superinfection with a second strain of HIV may lead to a more rapid increase in plasma HIV RNA levels, but apparently does not contribute much to CD4 T-cell loss or disease progression, according to a study published in the September 24 edition of AIDS.

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Electron Microscopy Provides Detailed Look at HIV in Gut Tissue

Imaging of active HIV infection of cells in gut tissue using 3-dimensional electron microscopy showed that the virus behaves differently in cultured cells and tissue infection models, providing new information about how HIV spreads within lymphoid tissue, according to a report in the January 30, 2014, edition of PLoS Pathogens.

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HIV Pandemic Likely Originated in Kinshasa, Spread Via New Transportation Routes

Kinshasa, in what is now the Democratic Republic of Congo, was likely the focus of early HIV-1 transmission beginning in the 1920s, leading to the wider global pandemic starting in the 1960s as railroad and river transportation became more widely used, according to a study published in the October 3 edition of Science.

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Low Drug Levels in Lymphatic Tissue May Underlie Low HIV Viral Load

HIV continues to replicate in the lymph nodes of people taking antiretroviral therapy (ART) that suppresses viral load in peripheral blood, according to a small study in the January 27 early online edition of Proceedings of the National Academy of Sciences. Several commonly used antiretroviral drugs reached lower concentrations in lymphatic tissue compared with blood, allowing ongoing virus production that may contribute to increased inflammation and immune activation in people with apparently well-controlled HIV.

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