Four recent studies have given the scientific community a better understanding of how human immunodeficiency virus (HIV) establishes and maintains itself in an infected individual and how antibody therapy may help prevent or fight the disease.
Current treatment for HIV infection depends on antiretroviral drug therapy (ART) to contain the infection in a host’s body. The approved anti-HIV drugs that are available act by blocking new rounds of infection but do not eliminate already-infected cells. Many of the infected cells are killed in the process of producing the virus, while some are cleared by the immune system once they express parts of viral proteins.
However, 20 years ago, research indicated that not all infected cells die or are cleared by the immune system; some become quiescent, do not express viral proteins (making them invisible to the immune system), and persist for decades despite continuous ART. When ART is stopped, the latent virus in these cells can become reactivated and reinitiate a spreading infection in the individual, hence the requirement for lifelong ART. To address this challenge, many researchers are studying ways to induce this latent virus to be expressed and ways to eliminate the infected cells once they express the virus.
In March, the laboratory of Robert Siliciano, M.D., Ph.D., of the Johns Hopkins University School of Medicine, published a study that sheds light on an additional challenge in dealing with HIV-1 that can persist in the host’s body despite ART.
By stimulating cultures of cells from infected individuals on ART, the team showed—in contrast to previous thinking—that the latent virus remains dormant even when cells divide and that the proliferation of cells harboring a relatively limited set of viral clones, in which the cells divide without necessarily expressing the latent virus, contributes importantly to viral persistence despite continued ART.
The laboratory of Brandon Keele, Ph.D., senior principal scientist, Retroviral Evolution Section, AIDS and Cancer Virus Program, Frederick National Lab, provided key viral sequence analysis that enabled critical parts of the work.
Keele’s laboratory also made important contributions to another paper published recently in PLoS Pathogens by John Mellors, M.D., of the University of Pittsburgh, and colleagues in the HIV Dynamics and Replication Program at the National Cancer Institute at Frederick that described similar findings in a similar patient group. Together, the results highlight yet another hurdle to curing HIV infection.
Other research suggests that there may be a way to prevent such challenges from ever occurring. Malcolm Martin, M.D., of the Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, led a collaborative study with Michel Nussenzweig, M.D., Ph.D., of The Rockefeller University, published in Nature, in which they demonstrated the utility of broadly neutralizing monoclonal antibodies (bNAbs) to prevent and treat HIV infection.
It has proven extremely difficult to develop bNAbs through vaccination, but infected individuals have developed them over extended periods. Unfortunately, such antibodies typically do not benefit the individual who develops them, as by the time he or she develops the antibodies, the virus has mutated to escape from them. However, bNAbs can be isolated from such individuals and produced in nearly unlimited quantities. Such bNAbs have shown promise for preventing infection in nonhuman primate models.
In the study, the team evaluated bNAb prophylaxis as a method to protect against HIV infection, with an emphasis on determining the duration of protection afforded by a single dose of antibody. To do so, they injected rhesus macaque monkeys with one of four bNAbs, 3BNC117, 10-1074, VRC01, and VRC01-LS (a laboratory-modified version of VRC01) and repeatedly exposed the monkeys to simian/human immunodeficiency virus (SHIV), a laboratory-created virus that infects monkeys but carries the envelope glycoprotein of HIV, the part of HIV targeted by bNAbs.
The researchers found that just a single dose of bNAb prophylaxis can provide protection from SHIV infection for up to 23 weeks of repeated exposure, using a potent antibody engineered to persist in the body. It could also be possible to administer repeated bNAb prophylaxes to provide longer-term protection against HIV.
“The study provides guidance on dose and dose schedule optimization for use of such antibodies to prevent human HIV infection,” said Jeffrey Lifson, M.D., a member of the research team and director of the AIDS and Cancer Virus Program at the Frederick National Lab.
In a separate study, the same collaborating groups administered a two-week course of two broadly neutralizing anti-HIV-1 antibodies, 3BNC117 and 10-1074, to rhesus macaques shortly after they had been SHIV infected. Normally, this infection would result in rapid damage to the host’s immune system, with destruction of CD4+T cells, a type of white blood cell integral in the body’s immune response, but the monkeys treated with bNAb therapy had significantly lower levels of cell damage and infection than those that received no treatment.
Even more promising, their infection levels remained low for months after treatment—even after the antibodies had decayed to ineffective levels—potentially because the undamaged CD4+T cells had successfully triggered an immune response against the invading SHIV.
Although it requires more study, the results suggest that it may be possible to improve an individual’s ability to control HIV infection, if caught early enough, by conditioning his or her immune system to fight it off.
Top image: Electron micrograph images of human T cells. Left: A healthy T cell. Right: An HIV-infected TH9 cell.
Bottom Image: The VRC01 antibody (blue and green) binds to HIV (grey and red).
By Samuel Lopez, Staff Writer; images courtesy of the National Institute of Allergy and Infectious Diseases