UC Berkeley

HIV kills more than 2 million people worldwide, annually. Progressive HIV disease is marked by the loss of peripheral CD4+ T cells, leading to immune dysfunction and leaving the host susceptible to opportunistic infections. Immune activation is thought to play a major role in T cell depletion and the ability of the host to control immune activation during chronic infection may enhance survival. How may a host learn to control immune activation? Pregnancy appears to be a time in which immune activation is tightly regulated as the immune systems of mom and her genetically non-identical fetus learn to become tolerant of one another's tissues. The trafficking of cells from mom across the placenta and into the fetus during gestation, a concept known as "maternal microchimerism," exposes the immune system of the developing fetus to maternal alloantigens and has been shown to promote tolerance by the fetal immune system to maternal cells. We hypothesized that if the fetus were exposed to antigens from HIV in utero that it might become tolerant to HIV antigens in a similar fashion to maternal cells and that this tolerance of HIV antigens would reduce the damage caused by immune activation if this fetus were infected with HIV later in life. To test this hypothesis, rhesus macaques (Macaca mulatta) were studied to determine if maternal microchimerism exists in this species and if exposure to SIV in fetal macaques can induce tolerance to the virus and reduce activation-induced damage after infection postnatally. Our data indicate that maternal microchimerism is detectable in low frequencies in fetal tissues and peripheral blood but can be found in relatively high frequencies in postnatal tissues. Fetal exposure to the nonpathogenic SIV clone, SIVmac1A11, was associated with reduced viral loads (p<0.02) and altered immunologic parameters after pathogenic SIVmac239 challenge. While we did not find evidence of immune tolerance to SIV antigens in these animals our data indicate that prenatal exposure to the virus has a lasting impact on the immune system that may allow for control of viral replication after pathogenic challenge. These data also indicate that the rhesus macaque is a tractable system for studying immunologic development in the context of prenatal infections that may be directly relevant to humans.