Showing papers by "James Blanchard published in 2005"

Impact of thymectomy on the peripheral T cell pool in rhesus macaques before and after infection with simian immunodeficiency virus.

Abstract: The goal of this study was to define, by surgical removal of the thymus in juvenile rhesus macaques, the role of the thymus in peripheral T cell homeostasis and to assess the significance of thymic output in SIV infection. By monitoring the changes in phenotypic T cell markers as well as in the numbers of TCR excisional circles – a recently described marker for recent thymic emigrants – following thymectomy, we present evidence that surgical thymectomy in juvenile macaques results in a faster decay of peripheral CD4+ cells, but does not cause a substantial shift in CD45RA+ and CD45RA– populations. We were able to measure a thymic output of 0.32% and 0.21% per day of CD4+ and CD8+ cells, respectively. No compensatory extra-thymic source was detected in lymphoid tissues, although there was a small compensatory increase in T cell proliferation in the peripheral T cell pool. After SIV infection, thymectomized animals did not have higher viral loads, greater T cell decay, or faster disease progression. We therefore conclude that peripheral destructive processes, rather than a loss of thymic output, appear to be the main causes of T cell depletion in SIV infection. See accompanying Commentary: http://dx.doi.org/10.1002/eji.200425643

V3 Loop-Determined Coreceptor Preference Dictates the Dynamics of CD4+-T-Cell Loss in Simian-Human Immunodeficiency Virus-Infected Macaques

Abstract: We used experimental infection of rhesus macaques with envelope gp120 V3 loop isogenic simian-human immunodeficiency virus (SHIV) molecular clones to more clearly define the impact of human immunodeficiency virus type 1 coreceptor usage in target cell selectivity and the rates of CD4-T-cell depletion. Functional assays demonstrate that substitution of the V3 loop of the pathogenic CXCR4-tropic (X4) SHIVSF33A2 molecular clone with the corresponding sequences from the CCR5-tropic (R5) SHIVSF162P3 isolate resulted in a switch of coreceptor usage from CXCR4 to CCR5. The resultant R5 clone, designated SHIVSF33A2(V3) ,i s replication competent in vivo, infecting two of two macaques by intravenous inoculation with peak viremia that is comparable to that seen in monkeys infected with X4-SHIVSF33A2. But while primary infection with the X4 clone was accompanied by rapid and significant loss of peripheral and secondary lymphoid CD4 T lymphocytes, infection with R5-SHIVSF33A2(V3) led to only a modest and transient loss. However, substantial depletion

HIV Vaccine Rationale, Design and Testing

Abstract: A central obstacle to the design of a global HIV vaccine is viral diversity. Antigenic differences in envelope proteins result in distinct HIV serotypes, operationally defined such that antibodies raised against envelope molecules from one serotype will not bind envelope molecules from a different serotype. The existence of serotypes has presented a similar challenge to vaccine development against other pathogens. In such cases, antigenic diversity has been addressed by vaccine design. For example, the poliovirus vaccine includes three serotypes of poliovirus, and Pneumovax(ρ) presents a cocktail of 23 pneumococcal variants to the immune system. It is likely that a successful vaccine for HIV must also comprise a cocktail of antigens. Here, data relevant to the development of cocktail vaccines, designed to harness diverse, envelope-specific Bcell and T-cell responses, are reviewed.