Vanessa M. Hirsch. D.V.M., D.Sc.
Senior Investigator
Dr. Hirsch received her D.V.M. from the University of Saskatchewan in Canada in 1977 and did a residency in pathology at the University of Saskatchewan, becoming board certified by the American College of Veterinary Pathologists in 1984. She earned her D.Sc. degree from Harvard School of Public Health, Boston, MA, in 1988. She was a research assistant professor at Georgetown University until 1992, when she joined the NIAID Laboratory of Infectious Diseases, transferring to the Laboratory of Molecular Microbiology (LMM) in 1999 and becoming tenured in 2002.
Description of Research Program
My group uses simian immunodeficiency virus (SIV) infection of monkeys as a model to study the pathogenesis of human AIDS and to develop effective vaccine strategies. SIV-infection of macaques, an Asian monkey species, is an artificial experimental animal model for AIDS. SIVs actually originate in primates of African origin, including sooty mangabeys (SIVsm), and African green monkeys (SIVagm). Remarkably, SIV infection of natural host species is generally not associated with disease despite robust viremia. In contrast, SIV-infection of macaques induces an immunodeficiency syndrome in these monkeys that is remarkably similar to that seen in HIV-infected humans. My laboratory investigates host and viral factors that contribute to disease progression in SIV infection of macaques and uses this model for evaluating vaccine strategies. For these studies, we use SIV isolates derived from naturally-infected sooty mangabeys at the Tulane primate center, the molecular clone SIVsmE543-3, and uncloned SIVsmE660. These SIVs provide an alternative to the more commonly used SIVmac239, particularly for heterologous challenge in vaccine settings. In addition, we study the mechanisms underlying the lack of disease in natural host species, using African green monkeys as a model.
Studies of Natural Hosts of SIV
My lab has a long-standing interest in the origins of primate lentiviruses, including HIV-1, and examines their close relatives in African monkeys. We have characterized a number of these strains of SIV over the years, including the first SIV isolate from a sooty mangabey monkey (SIVsm), a number of isolates from African green monkeys (SIVagm), and a number of other strains from various African monkeys.
My laboratory demonstrated that SIVagm, while apathogenic in AGM, induces AIDS in macaques. This discrepancy allows us to examine the mechanisms of attenuation in the natural host species. We conducted comparative studies of AGM and pigtailed macaques (PTM) infected with the same isolate and found that PTM develop AIDS, with disease progression linked to the extent of viremia (Goldstein et al., 2005). In contrast, AGM remain healthy with comparable levels of viremia as found in PTM. The two infections also differ in the degree of chronic immune activation (Goldstein et al., 2006). Recent studies have focused on delaying the adaptive immune response by depleting CD8+ T cells and B cells during primary infection. Depletion does not result in disease progression in AGM. In contrast, a similar depletion results in significantly higher viremia and accelerated disease progression in PTM. Thus, the dependence on adaptive immune responses for controlling viremia is a factor that differs in these two primates.
Pathogenesis of SIV in Macaques
Rapid Disease Progression
Disease progression in pathogenic models of AIDS in macaques is variable, ranging from under six months to more than seven years. These rapid progressor (RP) animals exhibit uncontrolled viral replication and failure of cellular and humoral immune responses. Pathologic comparison of tissues from RP macaques as compared with those of macaques that progress at a conventional pace (CP) revealed significantly higher endstage viral load in RP macaques. The vast majority of SIV-infected cells in RP macaques were macrophages, compared with a predominance of T cells infected in CP macaques. We evaluated the role of virus in the development of this syndrome by generating infectious molecular clones from an RP macaque. Inoculation of macaques did not reproduce the rapid disease phenomenon, but rapid evolution of this virus in association with developing antibody responses suggests that this virus is less fit. This study suggests that the evolution of RP-specific variants is the end result of replication in a severely immune compromised host, rather than the direct cause of rapid progression.
Figure 1. Comparison of the kinetics of plasma viral RNA levels in RP (red) and CP (blue) macaques. Credit: NIAID
Mechanisms of CD4 Depletion in Chronic SIV Infection.
The progressive decline of CD4 T cells is a hallmark of disease progression in HIV and SIV infection. Whereas the acute phase of the infection is dominated by virus-mediated depletion of memory CD4 T cells, chronic infection is often associated with a progressive decline of total CD4 T cells, including the naïve subset. The mechanism of this second phase of CD4 T cell loss is unclear. We studied patterns of CD4 T cell subset depletion in blood and tissues of SIV-infected macaques and observed two patterns of CD4 T-cell depletion, primarily affecting either naïve or memory CD4 T cells. Progressive decline of total CD4 T cells was observed in a subset of macaques and was associated with plasma antibodies autoreactive with CD4 T cells. More importantly for AIDS pathogenesis, the level of autoreactive antibodies significantly correlated with the extent of naïve CD4 T-cell depletion. These results suggest an important role of autoreactive antibodies in the CD4 T-cell decline observed during progression to AIDS (Kuwata et al., 2009).
SIV NeuroAIDS
SIV infection of macaques may result in SIV encephalitis (neuroAIDS), although this is a feature more commonly observed in macaques with rapid progressive disease. We reported on two conventional progressors (H631 and H636) with encephalitis in rhesus macaques inoculated with a derivative of SIVsmE543-3. Phylogenetic analyses of viruses isolated from the cerebral spinal fluid (CSF) and plasma from both animals demonstrated tissue compartmentalization (Dang et al., 2008). Additionally, virus from the central nervous system (CNS) was able to infect primary macaque monocyte-derived macrophages more efficiently than virus from plasma. We speculated that these viruses were under different selective pressures in their separate compartments. We are currently studying virus isolated from the brain or CSF of one of these animals as a model for neuroAIDS.
| 
Figure 2. Phylogenetic tree showing the compartmentalization of viruses found in the brain and cerebral spinal fluid (CSF) versus the plasma in a conventional macaque with SIV encephalitis. Credit: NIAID |
Figure 3. Confocal microscopy demonstrating multinucleated giant cells labeled with Ham56 (white) expressing SIV RNA (green) that are surrounded by T cells stained for CD3 (red) in the brain of a macaque with SIV encephalitis. Credit: NIAID
Vaccine Development
A primary goal of studies with SIV infection of macaques is the development of a vaccine for AIDS, and this is the other focus of my research. Unfortunately, many of the vaccine approaches tested thus far have resulted in only partial protection from infection in primate models of AIDS.
My laboratory has focused on live viral vectors to prime a cell-mediated immune response, specifically the highly attenuated vaccinia virus, modified vaccinia Ankara (MVA). We initially demonstrated that vaccination with MVA-expressing SIV genes resulted in significant modulation of viremia and improved survival when these animals were challenged with pathogenic SIV (Ourmanov et al., 2000). Long-term follow-up of this cohort of animals over the subsequent nine years showed that they maintained a survival advantage, although all but two of the macaques have progressed to AIDS (Ourmanov et al., 2009). Importantly, improved survival correlated with preservation of memory CD4+ T cells in the peripheral blood. The greatest survival advantage was observed in macaques immunized with regimens containing SIV Env: the titer of neutralizing antibodies to the challenge virus prior to challenge correlated with preservation of CD4 T cells. These data are consistent with a role for neutralizing antibodies in non-sterilizing protection from high viremia and associated memory CD4+ T-cell loss. Future studies will focus on generating homologous neutralizing antibody responses to determine their role in protection from SIV infection.
Research Group Members
Left to right: Que Dang, Charles Brown, Robert Goeken, Simoy Goldstein, Vanessa Hirsch, Ilnour Ourmanov, Sonya Whitted
Selected Publications
(View list in PubMed.)
Ourmanov I, Kuwata T, Goeken R, Goldstein S, Iyengar R, Buckler-White A, Lafont B, Hirsch VM. Improved survival in rhesus macaques immunized with modified vaccinia virus Ankara recombinants expressing simian immunodeficiency virus envelope correlates with reduction in memory CD4+ T-cell loss and higher titers of neutralizing antibody. J Virol. 2009 Jun;83(11):5388-400.
Kuwata T, Nishimura Y, Whitted S, Ourmanov I, Brown CR, Dang Q, Buckler-White A, Iyengar R, Brenchley JM, Hirsch VM. Association of progressive CD4(+) T-cell decline in SIV infection with the induction of autoreactive antibodies. PLoS Pathog. 2009 Apr;5(4):e1000372.
Dang Q, Goeken RM, Brown CR, Plishka RJ, Buckler-White A, Byrum R, Foley BT, Hirsch VM. Adaptive evolution of simian immunodeficiency viruses isolated from two conventional-progressor macaques with encephalitis. J Infect Dis. 2008 Jun 15;197(12):1695-700.
Brown CR, Czapiga M, Kabat J, Dang Q, Ourmanov I, Nishimura Y, Martin MA, Hirsch VM. Unique pathology in simian immunodeficiency virus-infected rapid progressor macaques is consistent with a pathogenesis distinct from that of classical AIDS. J Virol. 2007 Jun;81(11):5594-606.
Goldstein S, Brown CR, Ourmanov I, Pandrea I, Buckler-White A, Erb C, Nandi JS, Foster GJ, Autissier P, Schmitz JE, Hirsch VM. Comparison of simian immunodeficiency virus SIVagmVer replication and CD4+ T-cell dynamics in vervet and sabaeus African green monkeys. J Virol. 2006;80(10):4868-77.
Goldstein S, Ourmanov I, Brown CR, Plishka R, Buckler-White A, Byrum R, Hirsch VM. Plateau levels of viremia correlate with the degree of CD4+-T-cell loss in simian immunodeficiency virus SIVagm-infected pigtailed macaques: variable pathogenicity of natural SIVagm isolates. J Virol. 2005 Apr;79(8): 5153-62.