A new understanding of how some infants may resist HIV disease

When a person is infected with a virus their immune system is normally activated to respond to and control the infection. However, when a person is persistently infected with HIV, the chronic activation and overstimulation of the immune system is associated with disease progression. HIV is unique in that it directly attacks the cells of the immune system, breaking down the body’s defenses. Once the adaptive immune system is alerted to an HIV infection, it responds by producing HIV-specific CD4+ T cells. While these T cells play a role in suppressing HIV, they are also preferentially targeted and destroyed by the virus. Thus, as more CD4+ T cells are generated in response to HIV, there are also more cells for the virus to infect and kill, setting off a destructive cycle.

This destructive cycle of chronic immune activation and virus replication may play a crucial role in HIV pathogenesis. The ultimate goal is to develop a vaccine that will prevent infection or allow the body to control the infection similar to what happens with common vaccines such as those for influenza—without inciting deleterious immune activation.

CNPRC Affiliate Scientist J. “Mike” McCune, MD, PhD (UCSF) and collaborating Core Scientists Alice Tarantal, PhD, and Dennis Hartigan-O’Connor, MD, PhD, recently published a study that supports the possibility that reducing immune activation may offer a new avenue to resistance against HIV.

Traditionally, vaccines are designed to induce an immune response that can specifically recognize and destroy a given target, for example, an infectious agent. Although highly successful against many acute infectious agents such as measles, this approach has not only failed to protect against HIV but also, in some instances, been associated with more infections, not less.

Because traditional vaccines generally induce activation of the immune system, they may paradoxically favor replication and spread of HIV. If this is the case, then protection against HIV may best be achieved by an immune response that is wholly different from those normally induced by traditional vaccines.

An alternative vaccination approach that was addressed in these studies is to prevent the replication and spread of HIV in vivo by creating a vaccine that suppresses a hyperreactive response against the virus, for example, one that generates tolerance to the virus in an antigen-specific manner. If such a response were to dampen the rate of viral spread, then the virus might be cleared by the normal processes of cell death and renewal.

Several routes of immunization have historically been associated with the induction of tolerance, including exposure to the antigen in utero. This route is one that occurs as a matter of course during gestation of the human fetus in an untreated, HIV-infected mother. Because more than 50% of those around the world who are infected by HIV are women of childbearing age (who, unfortunately, are often not on suppressive antiretroviral therapy during the course of pregnancy), such exposures are also common. Yet, remarkably, only about 5 to 10% of babies born to such mothers are found to have been infected prenatally.

Building on the knowledge that fetal exposure to infectious pathogens in utero can result in reduced immune responses, or tolerance, to those pathogens postnatally, the team hypothesized that fetal exposure to simian immunodeficiency virus (SIV), a close relative of HIV, may render the fetus tolerant to the virus, becoming less reactive to, or tolerant of, proteins derived from SIV and reducing damage caused by immune activation.

In these studies, fetal rhesus monkeys were exposed to nonpathogenic SIV very early in gestation (late first trimester). When experimentally inoculated with pathogenic SIV after birth, the team expected that exposed monkeys would mount less aggressive immune responses against the virus, have lower immune activation, and have less severe disease than unexposed animals. They actually found that the monkeys exposed to SIV in utero did not display any direct evidence of tolerance to SIV; however, the animals did have significantly lower viral loads after infection with pathogenic SIV postnatally, and altered immune responses that were associated with the control of viral replication.

These studies, although preliminary, provide an important avenue of research to pursue. One might envision developing vaccines that induce an immunological tolerance (tolerogenic) response in people at risk for HIV infection. Similar vaccines might be useful against other chronic infectious agents where, as with HIV, pathology and spread of the pathogen are often associated with an activated immune system. Further work on tolerogenic vaccines might also find application in the prevention or treatment of one or more of the 80 inflammatory autoimmune diseases, including rheumatoid arthritis, systemic lupus, celiac disease, and inflammatory bowel diseases. This research also highlights the fetal proof-of-concept model developed by Dr. Tarantal to address preclinical questions such as the safety of new methods of cell and gene transfer and novel vaccines prior to Phase I clinical trials.

The research was published August 12, 2015 in the prestigious journal Science Translational Medicine (Baker CA, Swainson L, Lin DL, Wong S, Hartigan-O’Connor DJ, Lifson JD, Tarantal AF, McCune JM. Exposure to SIV in utero results in reduced viral loads and altered responsiveness to postnatal challenge. Sci Transl Med 2015 Aug 12;7(300):300ra125. doi: 10.1126/scitranslmed.aac5547).

Support was provided via grants from the National Institute of Allergy and Infectious Diseases (NIAID), the National Heart, Lung, and Blood Institute (NHLBI) Center for Fetal Gene Transfer for Heart, Lung, and Blood Diseases, the Bill and Melinda Gates Foundation, the UCSF Clinical and Translational Research Institute, the Harvey V. Berneking Living Trust, and the CNPRC base operating grant.