The Importance of Sex in HIV Cure Strategies

Based on sex differences, would women and men potentially benefit equally from different HIV cure strategies?

In the context of HIV, female sex has been associated with lower viral burden following an acute infection, delayed rebound of HIV following interruption of antiretroviral therapy (ART), a fourfold higher probability of being able to control HIV in the absence of ART, and higher overall life expectancy.

It has been known for decades that women have better outcomes than men following certain viral, bacterial, and fungal infections, including hepatitis B virus, tuberculosis, and cryptococcus. They also have enhanced antibody responses to common bacterial and viral vaccines.

In addition, the only two individuals worldwide documented to be infected with potent strains of HIV yet apparently capable of achieving a spontaneous cure of their infection were female—Loreen Willenberg and the Esperanza patient, a woman from Argentina whose name is derived from her hometown.

So, what mechanisms underlie those dramatic sex differences and what might this mean for curing women and men living with HIV?

Accounting for differences

With funding from amfAR, Dr. Xu G. Yu along with past amfAR grantee Dr. Mathias Lichterfeld, both of the Ragon Institute of MGH, MIT and Harvard, and Brigham and Women’s Hospital, designed a study to investigate what might account for the differences.

Thirty females and 35 males living with HIV and receiving ART for at least 20 years were studied.

The researchers looked at the makeup of the HIV reservoir, which is partly composed of dormant infected cells—intact proviruses—that persist beyond the reach of ART, but which can be reactivated once ART is stopped. Because the virus can rebound if not controlled by ART, the HIV reservoir forms the main barrier to a cure.

Two differences were noted based on sex.

First, reservoirs of latently infected cells in peripheral blood of females contained virus of much lower genetic complexity, which might make an HIV cure easier. Second, these reservoirs also had a higher proportion of intact proviruses integrated into “gene deserts”—regions of chromosomes from which it is very difficult to activate infectious virus. In other words, “gene deserts” lock down the virus, rendering it less likely to replicate.

When researchers looked at immune system makeup, they found that innate immune responses against HIV, particularly involving natural killer (NK) cells, were much stronger in females.

Next steps

The authors conclude that their study “reinforces the importance of considering sex in the design and implementation of cure-directed medical interventions and suggests that females may be better candidates to explore innate immunity-dependent strategies for targeting HIV-1 reservoir cells.”

Dr. Laurence is amfAR’s senior scientific consultant.

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