BETHESDA, MD—While the hunt for an HIV vaccine has run into a number of roadblocks the past few years, researchers are still meticulously searching for aspects of the virus and the transmission process that could prove to be viable targets for future interventions. NIH grantee Cynthia Derdeyn, PhD, is at the forefront of HIV vaccine research. She and her colleagues at Emory University have been exploring the dynamics of HIV sexual transmission—research that has led to a number of discoveries that could prove fruitful in the creation of a vaccine.
Virus as Escape Artist
One of the fascinating and frustrating aspects of the HIV virus is its genetic variance. The virus mutates within a single individual at an incredibly high rate, so the population of viruses in a single patient becomes genetically more diverse as time goes by. This creates a significant problem for the development of any vaccine treatment, and also results in resistance to current anti-viral drugs.
Several years ago, Derdeyn was one of a team of researchers who discovered that the virus goes through a “genetic bottleneck” at the time of infection. This meant that, at the moment of infection, the genetic variance of the virus within the newly infected individual was at an all-time low and might be more susceptible to therapies.
Derdeyn went on to focus the research on the very early immune responses individuals mount against the virus, and how HIV is able to escape from those responses. “We know from our work that most newly infected subjects mount a highly strain-specific neutralizing antibody response against the infecting virus, and the virus escapes. This is pretty well established. But our research gets to the question of why and how does this occur,” Derdeyn explained to an auditorium of HIV researchers on the NIH campus last month.
An ongoing study looking at discordant heterosexual couples in Zambia and Rwanda, where one partner was HIV-positive and the other was negative at time of enrollment, has allowed Derdeyn and her colleagues to get a look at HIV infection early in the process. “The couple will come in every few months and there will be counseling for the uninfected partner, and they’ll be given condoms to reduce the threat of transmission, but still about 8% of pairs would transmit every year,” she explained. “And because they come in frequently, we’re able to monitor them for infection. Sometimes we get people who are antigen positive and antibody negative—before they seroconvert.”
It is this research that has revealed a small window after infection when the virus stays homogeneous. “But as soon as you get immune responses, the virus diversifies again and becomes a quasispecies,” Derdeyn said.
The study investigators have attempted to map how the virus was eventually able to escape from neutralizing antibodies (Nab). Looking at three specific patients—two from Zambia and one from Rwanda—the researchers were able to recover monoclonal antibodies that were present in the patients at the early stages of infection.
“It looks like the early antibody response is at least of limited specificity if not monospecific in these patients and [the antibodies seem to target] exposed or external, surface areas of the virus,” Derdeyn explained.
Derdeyn and her colleagues have concluded that HIV infection leads to many different immunological outcomes, each with unique Nab targets and escape pathways. “This likely reflects the genetic diversity of the viral envelope and the host B cell response.”
The Role of B Cells
This finding has led Derdeyn’s team to begin looking at how B cells—lymphocytes that have a large role in humoral immune response—are affected by HIV infection. While it has been established that B cell dysfunction occurs in HIV infection, it is unknown what causes this and how it affects production of Nabs.
While research has been done in inhibitory receptors in T cell dysfunction, Derdeyn’s team was the first to take a close look at how those receptors—PD-1 and BTLA—are involved in B cell dysfunction urging chronic HIV infection. PD-1 is involved in the development of aberrant hyperactivation and immune exhaustion during chronic viral infections. BTLA (B and T lymphocyte attenuator) has been shown in mouse studies to be important in maintaining tolerance and avoiding autoimmunity.
Derdeyn found that both of the receptors are altered on B cells during HIV infection, with PD-1 seen at a higher rate and BTLA seen at a lower rate. There was also correlation with viral load, with a higher viral load showing higher PD-1 and a lower BTLA.
“These two inhibitor receptors, previously recognized mostly for their effect on T cells, could play a role in B cell dysregulation,” Derdeyn noted. “And these receptors may be considered for interventions.”