Unit: Pathogenesis of Lentiviral Infections
Director: HURTREL Bruno
The Unit has used the SIVmac model, involving the infection of macaques to focus its efforts on two problems fundamental to understanding the physiopathology of HIV infection but impossible to study in humans: 1) lymphocyte dynamics and the mechanisms by which viral replication is controlled during primary infection, the final aim of this work being the reorientation of vaccine studies and 2) the physiopathological mechanisms underlying HIV encephalopathy.
1. Analysis of the mechanisms controlling viral replication during primary infection with SIV; relationship to disease progression
This phase cannot be investigated in clinical studies in humans because it is generally asymptomatic and therefore undiagnosed. The macaque SIVmac251 infection model is almost identical to human HIV infection in physiopathological terms. During primary infection, the lymphoid organs are at the centre of the physiopathological process because they constitute the source of both viral dissemination and the effector cells of the immune system. Extremely precise analysis of viral replication and of the target cells, in lymph nods by means of a combination of immunolabelling and in situ hybridisation, and in the bloodstream, made it possible to correlate the capacity of each individual to eliminate the viral load during primary infection with subsequent disease progression. An exhaustive study of the virological and immunological events occurring in the days following infection identified two predictive factors: the precocity of viral replication and severe immunodepression following the start of viral replication seven to 14 days after infection that decreased or abolished immune responses directed against SIV and unrelated antigens. We have demonstrated that the intense apoptosis occurring during this period, by abolishing the antiviral immune response, affects the ultimate prognosis of the infection. This led us to investigate the cellular and molecular mechanisms underlying this cell death process. In parallel, we studied the dynamics of lymphocyte activation and proliferation during infections with the pathogenic virus SIVmac251 and the attenuated virus SIVmac?nef. Understanding these relationships (viral replication cellular activation immune response apoptosis) occurring during primary infection is fundamental for the development of a vaccine effective against HIV infection. Our work today aims to determine the role of chemokine receptors, which serve as the points of entry for HIV and SIV, as a means of identifying the host factors likely to reflect these differences in progression between individuals at a very early stage.
An understanding of the physiopathology of primary infection with pathogenic and non-pathogenic viruses should make it possible to approach vaccine development from a physiopathological viewpoint.
2) Physiopathology of encephalopathies due to lentiviral infections
The problems posed by the neurological disorders associated with AIDS, a major complication of this disease, are poorly understood. This is because analysis in humans is extremely difficult because we have access only to cerebralspinal fluid and post-mortem pathology samples. Macaques infected with SIVmac251 present encephalopathies identical to those described in humans, making it possible to carry out exhaustive longitudinal studies. Using this model, we have demonstrated the passage of infected cells, essential of monocyte origin, into the brain during primary infection. These infected cells triggered a latent encephalopathy. In situ hybridisation showed that, throughout infection, the virus was present and replicated at a low rate within the central nervous system (CNS) in cells of the monocyte lineage (macrophages and microglial cells). With the aim of testing the various hypotheses currently put forward to explain the neuropathogenicity of HIV, we quantified very rigorously the lesions present in the CNS in this model, and compared the results obtained with those for virus production. We demonstrated the absence of a relationship between plasma viral load and the cerebral lesions induced. One of the fundamental questions concerning the asymptomatic period is viral turnover in the CNS. Our recent work in macaques has demonstrated that the viruses found within the CNS originate essentially from primary infection. In contrast, none of the new pseudospecies characterised in the periphery were found in the CNS during the asymptomatic phase. These results provide new evidence that treatment should be initiated as soon as possible during primary infection.
Keywords: Virology, AIDS, primary-infection, apoptosis, encephalopathy