The predictive value of acute gut-associated lymphoid tissue (GALT) CD4+ T cell depletion in lentiviral infections was assessed by comparing three animal models illustrative of the outcomes of SIV infection: pathogenic infection (SIVsmm infection of rhesus macaques (Rh)), persistent nonprogressive infection (SIVagm infection of African green monkeys (AGM)), and transient, controlled infection (SIVagm infection of Rh). Massive acute depletion of GALT CD4+ T cells was a common feature of acute SIV infection in all three models. The outcome of this mucosal CD4+ T cell depletion, however, differed substantially between the three models: in SIVsmm-infected Rh, the acute GALT CD4+ T cell depletion was persistent and continued with disease progression; in SIVagm, intestinal CD4+ T cells were partially restored during chronic infection in the context of normal levels of apoptosis and immune activation and absence of damage to the mucosal immunologic barrier; in SIVagm-infected Rh, complete control of viral replication resulted in restoration of the mucosal barrier and immune restoration. Therefore, our data support a revised paradigm wherein severe GALT CD4+ T cell depletion during acute pathogenic HIV and SIV infections of humans and Rh is necessary but neither sufficient nor predictive of disease progression, with levels of immune activation, proliferation and apoptosis being key factors involved in determining progression to AIDS.

Intestinal CD4+ T cells are rapidly and profoundly depleted in HIV-infected patients and SIV-infected macaques. However, monitoring intestinal cells in humans is difficult, and identifying surrogate markers in the blood, which correlate with loss or restoration of intestinal CD4+ T cells could be helpful in monitoring the success of therapeutic strategies and vaccine candidates. Recent studies indicate HIV utilizes the intestinal homing molecule α4β7 for attachment and signaling of CD4+ T cells, suggesting this molecule may play a central role in HIV pathogenesis. Here we compared β7HIGH integrin expression on CD4+ T cells in blood with loss of CD4+ T cells in the intestine of macaques throughout SIV infection. The loss of β7HIGH CD4+ T cells in blood closely paralleled the loss of intestinal CD4+ T cells, and proved to be a more reliable marker of intestinal CD4+ T cell loss than monitoring CCR5+ memory CD4+ T cells. These data are consistent with a recent hypothesis that α4β7 plays a role in the selective depletion of intestinal CD4+ T cells, and indicate that monitoring β7HIGH expression on CD4+ T cells in the blood may be a useful surrogate for estimating intestinal CD4+ T cell loss and restoration in HIV-infected patients.

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It has never been determined if activation of the blood-brain barrier (BBB) during simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) infection is a function of high levels of circulating virus or if the virus has to be within a cell capable of crossing the BBB to activate it. In vitro models of the BBB are becoming recognized as an acceptable method for determining the cellular events associated with HIV neuroinvasion. Cell free virus (when added in the physiologically relevant lumen) although capable of activating the endothelial cells of our in vitro BBB did not activate astrocytes beneath. SIVmac251-infected CEMx174 cells, however, were capable of activating both components of the BBB model. Here we demonstrate that an in vitro model of the BBB can be activated in a physiologically relevant manner, that SIV requires to be cell-associated and that endothelial cells of the BBB are not the only components that are activated during SIV neuroinvasion.

A series of experiments were conducted to examine the pattern of production and secretion of interferon-tau (IFN-tau) by blastocysts following parthenogenetic activation of bovine oocytes. In the first experiment, 36.8, 24.1, and 33.2% of IVF-derived and parthenogenetically activated oocytes cultured in the presence or absence of a monolayer of buffalo rat liver cells, respectively, reached the blastocyst stage. Following individual culture of blastocysts, IFN-tau concentration in medium droplets was similar among the three groups, although IVF-derived blastocysts contained significantly more cells. In the second experiment, 156 IVF-derived blastocysts were sexed by PCR with 75 and 81, respectively, being male and female. IFN-tau secretion of these was compared to that of 70 parthenogenetic blastocysts. Female and parthenogenetic blastocysts produced significantly more IFN-tau than their male counterparts. In the third experiment, the ability of hatched blastocysts to form outgrowths and the pattern of their IFN-tau secretion were examined. Of the 48 IVF-derived blastocysts, 44 formed outgrowths compared to 41 of the 42 hatched parthenotes. Parthenogenetic outgrowths were significantly larger after 7 days, but this difference had disappeared after 14 days. IFN-tau secretion did not differ between the two groups. Lastly, sequence analyses of expressed mRNA from individual parthenogenetic blastocyst outgrowths showed four different transcript types which, based on their predicted amino acid sequence, belong to two subgroups, IFN-tau1 and IFN-tau3. In addition, one new transcript sequence was identified, encoding a new protein isoform.