Track A report by Patricia MONTEIRO
This session highlighted recent findings on the innate defense mechanisms that could be active against HIV infection. Franck Kirchhoff (Germany) focused on the lack of innate anti-viral immunity to HIV-1 infection as a result of effective countermeasures activated by the virus against host restriction factors. The restriction factor APOBEC3G, a cytidine deaminase that interferes with HIV replication by inducing lethal hyper-mutations of the viral genome, is degraded by the accessory viral protein Vif. Furthermore, HIV-1 infection of non-human primate cells is blocked by simian TRIM5α, a restriction factor that destabilizes viral capsids, although not by human TRIM5α. Tetherin can inhibit the release of new progeny virions, but its effect is antagonized by the viral accessory protein Vpu that interacts with tetherin; as a consequence tetherin cannot trap the virus on the cell surface. Moreover, during HIV evolution, both Nef- and Vpu-mediated tetherin antagonism could be observed. Indeed, SIVcpz, the immediate precursor of HIV-1, uses Nef rather than Vpu to counteract chimpanzee’s tetherin. Human tetherin, however, is resistant to Nef showing that tetherin is a significant but not insurmountable barrier to zoonotic transmission of SIVs to humans. Interestingly HIV-1 strains belonging to group M has a fully functional Vpu and represents the group of viruses most prevalent in humans. In contrast, HIV-2, which is less prevalent than HIV-1 M, has no Vpu and is also characterized by the lack of Nef effect on tetherin inhibition. In conclusion, humans and other mammals have evolved different factors counteracting HIV infection; however, as a countermeasure, HIV-1 evolved specific tools to antagonize these factors. Strategies aiming to strengthening the host defenses or inhibiting the viral antagonists might provide novel therapeutic opportunities to control HIV infection.
After this opening lecture, Olivier Schwartz (France) presented studies on cell-to-cell HIV transfer, that is a rapid mode of HIV transmission leading to viral replication, more efficient than that induced by cell-free virions. Plasmacytoid dendritic cells (pDC) are the principal cells producing interferon-alpha (IFN-alpha) when leukocytes co-cultured with a T cell line infected with HIV and to create poly-synaspses (multiple contact sites) with HIV-infected T cells increasing the transmission of the virus. Using HIV mutant strains, Schwartz demonstrated that HIV-1 envelope glycoproteins are required to promote efficient IFN-alpha production without the need for productive infection. This indicates that defective viruses are also sensed and can contribute to HIV-induced immune activation. They further showed that the innate sensing of HIV-infected cells depends on Tool-Like Receptors (TLRs) 7 and 8; TLR7 is active in pDC but in other cell types TLR7-independent mechanism exists.
H. Stoiber described results on the role of Complement in HIV infection. Complement activation can lead to the lysis of infected cells, opsonization, inflammation and cell activation. Trapping of HIV in vivo is mainly dependent on Complement Receptor (CR) expressed by follicular dendritic cells in germinal centers of the lymph nodes; as a consequence, Complement is responsible for maintaining the largest extracellular viral reservoir in HIV-infected individuals. Complement is also a natural adjuvant for the induction of retrovirus-specific cytotoxic T lymphocytes (CTLs). However, Complement can also protect degradation of free virions after interaction with them. Complement regulators, concluded Stoiber, can increase Complement-mediated cell lysis and could be therefore exploited to design pathogen-specific constructs.
A. Cunningham focussed on the role of dendritic cells in immune response and also on aspect that how trapping of HIV invivo is dependent on complement molecules from host like CD55 and CD59 which gets incorporated in budded virus envelope .
In sum, this session provided the overview of most prominent innate defence mechanisms and insights in the interplay between HIV and host factors.