Understanding Control of Virus Replication
What can researchers learn from studying how some species of nonhuman primates can control infection with SIV?
Progress toward developing an AIDS vaccine has been hampered by the lack of clarity about what immune responses are required to prevent HIV transmission or protect against disease progression. The specific immune responses that protect against a pathogen, such as HIV, are known as the immune correlates of protection (see VAXNovember/December 2006 Primers on Understanding Immune Correlates of Protection, Part I and II). Often times, even after a vaccine is in widespread use, researchers do not know precisely which immune responses induced by the vaccine are actually responsible for protection.
Yet researchers do know that almost all existing vaccines protect against disease by inducing antibodies—Y-shaped proteins that latch on to and disable the disease-causing agent. So far none of the AIDS vaccine candidates in development have been capable of inducing antibodies against HIV that can neutralize the virus. Therefore, researchers are trying to collect as much information as possible about the types of immune responses that might offer protection against HIV, or at least play a role in controlling infection once it occurs. Some of this information comes from studying both humans and nonhuman primates that when infected with HIV or simian immunodeficiency virus (SIV)—the monkey equivalent of HIV—are able to keep the virus in check. Researchers are hopeful that deciphering the immune responses in these individuals/animals that allow them to successfully control HIV/SIV will provide clues to aid in the design of improved AIDS vaccine candidates.
There are two categories of individuals that are especially critical to this endeavor: long-term nonprogressors and exposed seronegatives. Long-term nonprogressors are individuals who are HIV-infected but are able to control the virus for an extended period of time without taking antiretroviral therapy (see VAX September 2006 Primer onUnderstanding Long-term Nonprogressors). Exposed seronegatives are individuals who do not become HIV infected despite known, and sometimes repeat, exposure to HIV (see Spotlight, this issue). Large studies of both of these categories of individuals are currently ongoing and results from these trials may offer insight into which immune responses play a role in control of HIV or resistance to infection in these individuals.
In the meantime, researchers are also studying immune responses in nonhuman primates, including some species that are the monkey equivalent of long-term nonprogressors, to mine for additional clues about the characteristics of immune responses that are effective in controlling SIV infection.
HIV exclusively infects and causes disease in humans, yet studies in animal models are a critical component of the pre-clinical development of AIDS vaccine candidates (see VAX October 2006 Primer on Understanding AIDS Vaccine Pre-clinical Development). To study AIDS vaccine candidates in nonhuman primates, researchers test them against SIV. These studies are most often conducted in rhesus macaques because when they are infected with SIV, they respond similarly to HIV-infected humans. SIV-infected rhesus macaques have very high levels of virus in their blood, much higher even than the HIV levels seen in humans; have a marked decline in the number of CD4+ T cells, which are the primary targets of both SIV and HIV; and eventually develop the monkey version of AIDS. Many of the immune responses against SIV in macaques are also similar to those observed during HIV infection. This makes the rhesus macaque/SIV model the closest approximation to studying HIV infection in humans.
But other species of nonhuman primates, including specifically sooty mangabeys, African green monkeys, and mandrills, do not develop simian AIDS or any other deleterious consequences following SIV infection, making them similar to human long-term nonprogressors. SIV-infected sooty mangabeys, for instance, are able to maintain normal levels of CD4+ T-cells and do not show any signs of disease progression.
However, sooty mangabeys do have high levels of SIV in their blood, unlike long-term nonprogressors, who are classified by their ability to control HIV’s replication. The high levels of SIV observed in sooty mangabeys indicate that the virus is efficiently and rapidly replicating in these animals, yet they still do not develop AIDS.
It is unknown exactly how sooty mangabeys are able to avoid AIDS even in the face of high levels of SIV replication, but researchers have observed some key differences in these animals. SIV-infected sooty mangabeys do not experience chronic immune activation in response to SIV infection, in contrast to rhesus macaques and HIV-infected people. Following HIV infection, the immune system enters a state of high alert and quickly activates both innate and adaptive immune responses against the virus. As the immune system responds to HIV, it pumps out more infection-fighting cells, including CD4+ T cells, which in turn creates more targets for the virus. While activation of the immune system is critical to snuffing out infections, during a chronic condition like HIV infection there are also several detrimental effects to the immune system being in a constant state of alert.
Studies have also shown another key difference between sooty mangabeys and other nonhuman primate species. Sooty mangabeys have lower quantities of CCR5, a receptor protein that is used by SIV and HIV to gain entry into and infect cells such as CD4+ T cells. While this does not block transmission of the virus altogether, it does remove some of the fuel that the virus needs to replicate. Researchers surmise sooty mangabeys may have developed some mechanisms for manipulating CCR5 to protect against SIV that allow them to successfully live with the virus without getting sick.
Efforts to understand the mechanisms controlling immune activation in the sooty mangabeys, and other natural hosts of SIV, as well as any immune responses they mount against this related virus may help AIDS vaccine researchers design improved candidates that could control HIV.