A mouse model for the pathogenesis of immunodeficiency virus infection

T lymphocyte numbers in the human body are kept constant by homeostatic mechanisms balancing cell gain and loss. These mechanisms eventually fail in HIV infection, which is characterized by progressive immune deficiency attributable to a slow but relentless depletion of CD4+ T cells, the main viral targets. HIV infection is also associated with increased T cell turnover and a state of generalized immune activation. One of the fundamental questions in the field of HIV research is the relation between CD4+ T cell depletion and immune activation. It has been suggested that the virus has a direct effect by killing CD4+ T cells and increased T cell turnover reflects a homeostatic response to CD4+ T cell depletion. Alternatively, chronic immune activation may lead to enhanced turnover of T cells by ongoing proliferation-differentiation and cell death. In both cases, AIDS is the result of an exhaustion of the regenerative capacity of the immune system. To address these questions we examined the consequences of activated CD4+ T cell killing in a virus-free mouse model. Immunodeficiency viruses are highly selective for activated/memory and regulatory CD4+ T cells due to restricted expression of CCR5, the co-receptor for HIV and SIV, or CD134 (OX40, TNFRSF4), the cellular receptor for FIV. Activated CD4+ T cells were depleted by conditional reactivation of diphtheria toxin gene mediated by Tnfrsf4-driven Cre recombinase expression. Conditional ablation of activated CD4+ T cells resulted in accelerated turnover, with only a minimal apparent effect on their numbers, and was associated with a reduction in CD4:CD8 ratio and development of CD4+ T cell immune deficiency, resembling HIV infection. Importantly, activated CD4+ T cell killing also resulted in generalized immune activation, including lymph node enlargement, B cell expansion, elevated serum levels of proinflammatory cytokines and increased turnover and activation of CD8+ T cells, characteristic of HIV infection. CD8+ T cell activation correlated with lack of regulatory CD4+ T cell function and was prevented upon regulatory CD4+ T cell reconstitution. We therefore propose a causal link between memory and regulatory T cell depletion and immune deficiency and immune activation, respectively

Impact of Thymectomy on the Peripheral T Cell Pool in the Context of SIV Infection

The thymus is the primary lymphoid organ responsible for T cell production. It is of particular interest in the context of human immunodeficiency virus (HIV)-l infection, in which the progressive loss of CD4+ T cells leads to immunodeficiency and opportunistic infection. CD4+ T cell loss is thought to result from direct and indirect killing of C D 4 cells in the periphery as well as from pathogenic effects of the virus on the thymus. However, it is not fully understood which is the greater factor in viral-induced CD4+ T cell decay. The development of an assay to detect T cell receptor excisional circles (TREC) as a marker for recent T cell receptor (TCR) recombination in the thymus has proved to be an invaluable tool for the study of recent thymic emigrants. Here we describe the development of this technique in the rhesus macaque model and use this method in combination with other techniques to study the role of the thymus in maintenance of the peripheral T cell pool. This study has two major goals: to define the role of the thymus in peripheral T cell homeostasis in the juvenile rhesus macaque (Macaca mulatto) and to assess the significance of thymic output in the context of simian immunodeficiency virus (SIV) infection. To this end, we have studied the impact of surgical thymectomy on the peripheral T cell pool in a cohort of macaques. W e present evidence that thymic output in the juvenile macaque is measurable but quantitatively insignificant in the context of the total T cell pool. While SIV infection does have pathogenic effects on the thymus, these effects play a minimal role in the overall destruction of the peripheral T cell pool

Accelerated in vivo proliferation of memory phenotype CD4+ T-cells in human HIV-1 infection irrespective of viral chemokine co-receptor tropism.

CD4(+) T-cell loss is the hallmark of HIV-1 infection. CD4 counts fall more rapidly in advanced disease when CCR5-tropic viral strains tend to be replaced by X4-tropic viruses. We hypothesized: (i) that the early dominance of CCR5-tropic viruses results from faster turnover rates of CCR5(+) cells, and (ii) that X4-tropic strains exert greater pathogenicity by preferentially increasing turnover rates within the CXCR4(+) compartment. To test these hypotheses we measured in vivo turnover rates of CD4(+) T-cell subpopulations sorted by chemokine receptor expression, using in vivo deuterium-glucose labeling. Deuterium enrichment was modeled to derive in vivo proliferation (p) and disappearance (d*) rates which were related to viral tropism data. 13 healthy controls and 13 treatment-naive HIV-1-infected subjects (CD4 143-569 cells/ul) participated. CCR5-expression defined a CD4(+) subpopulation of predominantly CD45R0(+) memory cells with accelerated in vivo proliferation (p = 2.50 vs 1.60%/d, CCR5(+) vs CCR5(-); healthy controls; P<0.01). Conversely, CXCR4 expression defined CD4(+) T-cells (predominantly CD45RA(+) naive cells) with low turnover rates. The dominant effect of HIV infection was accelerated turnover of CCR5(+)CD45R0(+)CD4(+) memory T-cells (p = 5.16 vs 2.50%/d, HIV vs controls; P<0.05), naïve cells being relatively unaffected. Similar patterns were observed whether the dominant circulating HIV-1 strain was R5-tropic (n = 9) or X4-tropic (n = 4). Although numbers were small, X4-tropic viruses did not appear to specifically drive turnover of CXCR4-expressing cells (p = 0.54 vs 0.72 vs 0.44%/d in control, R5-tropic, and X4-tropic groups respectively). Our data are most consistent with models in which CD4(+) T-cell loss is primarily driven by non-specific immune activation

Thirty Years with HIV Infection—Nonprogression Is Still Puzzling: Lessons to Be Learned from Controllers and Long-Term Nonprogressors

In the early days of the HIV epidemic, it was observed that a minority of the infected patients did not progress to AIDS or death and maintained stable CD4+ cell counts. As the technique for measuring viral load became available it was evident that some of these nonprogressors in addition to preserved CD4+ cell counts had very low or even undetectable viral replication. They were therefore termed controllers, while those with viral replication were termed long-term nonprogressors (LTNPs). Genetics and virology play a role in nonprogression, but does not provide a full explanation. Therefore, host differences in the immunological response have been proposed. Moreover, the immunological response can be divided into an immune homeostasis resistant to HIV and an immune response leading to viral control. Thus, non-progression in LTNP and controllers may be due to different immunological mechanisms. Understanding the lack of disease progression and the different interactions between HIV and the immune system could ideally teach us how to develop a functional cure for HIV infection. Here we review immunological features of controllers and LTNP, highlighting differences and clinical implications

Tolerance has its limits: how the thymus copes with infection

The thymus is required for T cell differentiation; a process that depends on which antigens are encountered by thymocytes, the environment surrounding the differentiating cells, and the thymic architecture. These features are altered by local infection of the thymus and by the inflammatory mediators that accompany systemic infection. Although once believed to be an immune privileged site, it is now known that antimicrobial responses are recruited to the thymus. Resolving infection in the thymus is important because chronic persistence of microbes impairs the differentiation of pathogen-specific T cells and diminishes resistance to infection. Understanding how these mechanisms contribute to disease susceptibility, particularly in infants with developing T cell repertoires, requires further investigation.We thank Joana Neves and Nadine Santos for critical reading of the manuscript. This work was supported by Portuguese Foundation for Science and Technology (FCT) grant PTDC/SAU-MII/101663/2008 and individual fellowships to CN-A and CN. SMB was supported by National Institutes of Health Grant R01 R56 AI067731

Insufficient Production and Tissue Delivery of CD4+Memory T Cells in Rapidly Progressive Simian Immunodeficiency Virus Infection

The mechanisms linking human immunodeficiency virus replication to the progressive immunodeficiency of acquired immune deficiency syndrome are controversial, particularly the relative contribution of CD4+ T cell destruction. Here, we used the simian immunodeficiency virus (SIV) model to investigate the relationship between systemic CD4+ T cell dynamics and rapid disease progression. Of 18 rhesus macaques (RMs) infected with CCR5-tropic SIVmac239 (n = 14) or CXCR4-tropic SIVmac155T3 (n = 4), 4 of the former group manifested end-stage SIV disease by 200 d after infection. In SIVmac155T3 infections, naive CD4+ T cells were dramatically depleted, but this population was spared by SIVmac239, even in rapid progressors. In contrast, all SIVmac239-infected RMs demonstrated substantial systemic depletion of CD4+ memory T cells by day 28 after infection. Surprisingly, the extent of CD4+ memory T cell depletion was not, by itself, a strong predictor of rapid progression. However, in all RMs destined for stable infection, this depletion was countered by a striking increase in production of short-lived CD4+ memory T cells, many of which rapidly migrated to tissue. In all rapid progressors (P < 0.0001), production of these cells initiated but failed by day 42 of infection, and tissue delivery of new CD4+ memory T cells ceased. Thus, although profound depletion of tissue CD4+ memory T cells appeared to be a prerequisite for early pathogenesis, it was the inability to respond to this depletion with sustained production of tissue-homing CD4+ memory T cells that best distinguished rapid progressors, suggesting that mechanisms of the CD4+ memory T cell generation play a crucial role in maintaining immune homeostasis in stable SIV infection

Mathematical modeling of immunological reactions

3. Models of HIV infection and other infectious diseases 4. Models of T cell activation and proliferatio