Globally, there are nearly 40 million individuals living
with HIV/AIDS, a number that is growing by
approximately 3 million each year. The overarching
goal of my laboratory is to contribute meaningfully to
the global response to HIV. Though HIV is ultimately a
preventable disease, the sheer number of new HIV
infections demonstrates that a prophylactic vaccine is
desperately needed to augment existing prevention
programs.
Our current research is informed by two observations that
have been made during the last ten years. First, a defining
feature of the HIV pandemic is the extraordinary sequence heterogeneity
among global HIV isolates. We now appreciate that
the sequence variability in HIV and its cousin simian
immunodeficiency virus (SIV) is less random and
stochastic than once thought – in fact, we
believe that most of the variation that accumulates
within an individual and among individuals in a
population is the consequence of selection by host
immune responses. Studying the interplay of viral
genetics and pathogenesis may reveal novel targets for
vaccination, or, perhaps more importantly, identify
genetic signatures associated with disease control or
progression.
The second observation is that host genetics profoundly
influences the individual response to HIV and SIV.
Polymorphisms in genes associated with immunity, such as
those in alleles of major histocompatibility complex (MHC)
class I molecules, do not prevent HIV infection, but
instead play a role in controlling the viral burden in
infected individuals. Since most vaccines currently in
testing utilize viral burden as either a primary or
secondary endpoint for efficacy, individual genetic
differences that influence viral burden may greatly
complicate vaccine evaluation.
Though almost all preclinical HIV vaccine trials are
performed with nonhuman primates, the scarcity of these
animals makes genetic matching of vaccinees almost
impossible. We are exploring the potential of a nonhuman
primate rarely used in AIDS research, the Mauritian origin
Cynomolgus macaque, to overcome this problem. Tens of
thousands of Cynomolgus macaques live on the island of
Mauritius, however, these animals all descend from a small
founder population of animals introduced within the past
500 years. We now know that only seven distinct chromosomal
haplotypes account for almost all of the MHC diversity in
this population and that these animals are susceptible to
widely used SIV strains including SIVmac239 and SIVmac251.
We believe that as additional host genetic factors that
influence SIV and HIV disease progression are discovered,
the value of completely MHC-defined Mauritian origin
Cynomolgus macaques will become apparent. We are now
performing comprehensive studies of SIV pathogenesis in
these animals with the objective of determining the exact
extent to which viral and host genetics influence disease
progression.
Our studies of MHC genetics transcend HIV/AIDS. We are
working with biodefense, organ transplant, and reproductive
biologists interested in nonhuman primate MHC genetics. As
part of these studies, we are characterizing new MHC
genetic variants in a variety of macaque populations and
are developing genetic tests for these variants.
Finally, our scientific program benefits from active
participation in the HIV/AIDS community. We regularly
participate in local outreach efforts and recently
collected our first samples from HIV+ patients in
conjunction with clinicians from UW-Hospitals. Our first
project with these samples is a foray into 'viral
archaeology' -- we want to determine whether we can
reconstruct the sequence evolution of virus in an infected
person using only samples collected after several years of
infection. If successful, we will better understand how the
immune system and extrinsic factors shape the evolution of
HIV. We also coordinate UW-Madison participation in the
HIV Elite Controller Study.
Rounding out our HIV studies is a collaborative
project with researchers in Sao Paulo, Brazil to study
HIV superinfection among recently infected Brazilians.
