Infection with anal human papillomavirus (HPV), a virus that can cause anal and cervical cancers, is associated with a higher risk of new HIV infection in previously HIV-negative men who have sex with men (MSM), according to new UCSF research.

Reported online ahead of print in the journal AIDS, the findings are available now. They are scheduled for publication in an upcoming print issue.

In previous studies, other sexually transmitted infections have been associated with higher risk of HIV infection and HPV is the most common sexually transmitted infection.

“We looked at HIV-negative men who have sex with men who were at high risk for HIV infection and who had multiple risk factors. Our results showed a strong independent association for increased risk of HIV acquisition among those men who were already infected with anal HPV,” said the study’s lead investigator, Peter V. Chin-Hong, MD, associate professor of clinical medicine and director of the program in transplant and immunocompromised host infectious diseases at UCSF.

The 1400 study participants were part of the EXPLORE trial, a large clinical trial to test the efficacy of a behavioral intervention for HIV-negative MSM with sites in Boston, Denver, New York and San Francisco. Risk factors were calculated from those men who became HIV-infected over the course of the trial and infections were identified by blood tests.

“We think that HPV enhances susceptibility to HIV infection through two mechanisms. Anatomically, the virus causes anal lesions. These lesions bring blood vessels closer to the surface and also the lesions’ skin layer is thinner and more easily shredded, which frequently causes bleeding. These disruptions of the mucosal barrier could allow easier entry for HIV,” said Chin-Hong.

In addition, HPV activates the immune system. The inflammatory cells recruited to the HPV lesions - dendritic cells, macrophages and CD4 T cells - are the immune cells most susceptible to HIV infection.

HPV vaccine has been found effective in preventing acquisition of the virus by women. Clinical trials testing the effectiveness of the vaccine among MSM are currently under way.

“To date, the focus of attention on HPV has been almost exclusively on its key role in causing squamous cell cancer. This study points to another important means by which HPV infection may be associated with morbidity and mortality, i.e., through potentiation of HIV infection. A direct role for HPV in this process will need to be confirmed in additional studies, and additional studies will be needed to understand the mechanisms by which HPV may do this, said the study’s senior investigator and author, Joel Palefsky, MD, professor of medicine and director of the Anal Neoplasia Clinic at UCSF.

“But it is encouraging to note that to the degree that HPV truly plays a role in increasing the risk of acquiring HPV infection, primary prevention of HPV infection through HPV vaccination may potentially reduce that risk,” he added.

Co-authors of the study include Marla Husnik, Fred Hutchinson Cancer Research Center in Seattle; Ross D. Cranston, University of Pittsburg; Grant Colfax and Susan Buchbinder, San Francisco Department of Public Health; Maria Da Costa and Teresa Darragh, UCSF; Dana Jones, Centers for Disease Control; Franklyn Judson, Denver Department of Public Health; Beryl Koblin, New York Blood Center; and Kenneth H. Mayer, Fenway Community Health Center in Boston.

This research was supported by funding from the University of California Universitywide AIDS Research Program, CYTYC Corporation, National Institute of Allergy and Infections Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institute of Child Health and Human Development, National Institute on Drug Abuse, the National Institute of Mental Health, Office of AIDS Research and National Center for Research Resources.

Source:
Jeff Sheehy

University of California - San Francisco

Scientists may need to rethink the design of drugs meant to block HIV from infecting human cells, according to a study that appears in the May 1st issue of the journal Cell, a Cell Press publication. That’s because the new report shows that HIV doesn’t enter cells in the way that experts had generally assumed it did.

Rather than fusing directly with the plasma membrane at cells’ outer surfaces to release its contents, HIV fusion primarily occurs via smaller, membrane-bound compartments inside of cells known as endosomes, the new research shows. The discovery implies that anti-HIV drugs known as fusion inhibitors might be more effective in blocking HIV if they too can do their work inside of cells, where fusion takes place.

“We show that HIV fusion occurs virtually exclusively from endosomes,” said Gregory Melikian of the University of Maryland School of Medicine. “It appears that it is this path to entry that leads to infection.”

“In order to efficiently block intracellular fusion events, the next generation of HIV entry inhibitors must be able to permeate the cell membrane,” he continued. Drugs that act on the endocytic machinery itself might also prove useful in limiting HIV infection.

Endosomes form in a process known as endocytosis by which cells take in material by engulfing and pinching off a portion of the cell membrane to form a smaller vesicle. Enveloped viruses that depend on low pH for entry are known to initiate infection by fusion with acidic endosomes. However, entry sites for pH-independent viruses, including HIV, had not yet been clearly defined.

In the new study, Melikian and his colleagues relied on a series of imaging studies to literally watch as HIV-1, the virus that normally infects humans, enters cells. Those experiments showed that complete viral fusion occurs not on the cell surface, but in endosomes. While HIV’s envelope sometimes did mix with the cell’s plasma membrane, in those cases delivery of the viral contents did not occur.

“Time-resolved imaging of single viruses and differential blocking of fusion by site-specific and universal inhibitors revealed that HIV-1 co-opts the endocytic machinery to enter into and fuse with target cells,” the researchers wrote. “By contrast, fusion with the plasma membrane did not progress beyond the lipid mixing step, suggesting that endosomal entry is the pathway that leads to productive infection.”

HIV-1 interacted with receptors on the cell surface leading to its internalization long before endosomal fusion, they show. That process minimized the surface exposure of conserved viral epitopes - portions of macromolecules that are recognized by the immune system - during fusion and reducing the efficacy of inhibitors targeting these epitopes.

The researchers also found that HIV-1’s release from endosomes depend on dynamins, enzymes that are important to the formation of new endosomes and their fusion with other membranes. Melikian said that dynamins may provide an additional driving force to expand pores and permit the release of the HIV-1 core out into the cell.

While Melikian said he hopes the findings will have practical implications, it does deliver some bad news for those on a mission to fight HIV. That’s because the endosomal path to entry would offer the virus several advantages, including sheltering HIV from antibodies and inhibitors that target key portions of the virus during the unusually slow fusion reaction.

The new result may also have relevance for other so-called pH-independent viruses, all of which were assumed to enter via fusion with the plasma membrane, Melikian said. After all, he noted, HIV has been a “poster child” for that group. “This may be a universal trend. Endosomes may be universally more conducive to viral entry.”

The researchers include Kosuke Miyauchi, Yuri Kim, Olga Latinovic, Vladimir Morozov, and Gregory B. Melikyan, of the University of Maryland School of Medicine, Baltimore, MD.

Source:
Cathleen Genova

Cell Press