HIV-1, the major causative agent of AIDS, has infected more than 60 million people and caused around 20 million deaths (WHO report 2009) worldwide. The development of highly active antiretroviral therapy (HAART) has significantly improved life expectancy in industrialized countries. However, HAART does not eradicate the virus, is only available for a small number of HIV-infected individuals and has severe side effects. Another major problem is the emergence of drug resistant HIV-1 strains. Overall, the high prevalence of HIV-1 and the lack of an AIDS vaccine emphasize the urgent need for novel therapeutic strategies. Some clues might come from studies of monkeys naturally infected with simian immunodeficiency viruses (SIVs). To date, SIVs have been detected in about 40 different non-human primate species. Three of them, SIVcpz from chimpanzees, SIVgor from gorillas and SIVsmm from sooty mangabeys have been transmitted to humans several times during the first half of the 20th century and gave rise to HIV-1 and HIV-2, respectively. Notably, SIVs seem to persist efficiently in their natural primate hosts without causing disease.  Understanding the basis for the lack of disease progression in natural SIV infection might help to elucidate how AIDS can be prevented in humans.
One of our major research interests is to clarify how „pathogenic“ HIV-1 strains and „non-pathogenic“ primate lentiviruses manipulate immune functions and to elucidate why simian immunodeficiency viruses (SIVs) can persist efficiently in their simian hosts without causing disease. It is known that HIV-1, the causative agent of AIDS, increases the responsiveness of infected T cells to activation. Recently, we showed that nef alleles from most primate lentiviruses exhibit a quite different phenotype and efficiently down-modulate TCR-CD3 to inhibit T cell activation and activation-induced cell death. This fundamental difference in Nef function might explain why high levels of immune hyper-activation are observed in progressing HIV-1 infection but absent in asymptomatic naturally SIV-infected monkeys. We have also examined why only one of at least four independent zoonotic transmissions of SIVs found in chimpanzees or gorillas to humans is responsible for the AIDS pandemic. Our results showed that only pandemic HIV-1 M strains evolved a fully functional Vpu that counteracts tetherin (a cellular factor that blocks virus release) and degrades CD4 (the primary receptor of HIV) to promote the release of fully infectious viral particles. Vpus from non-pandemic HIV-1 O and P strains are poor tetherin antagonists, whereas those from the rare group N viruses do not degrade CD4. This finding may explain why group M viruses are almost entirely responsible for the global HIV/AIDS pandemic.

Profilbild von Prof.Dr. Frank Kirchhoff

Prof.Dr. Frank Kirchhoff


Figure 1. Evolution of HIV-1

SIVcpz represents a recombinant of the precursors of viruses nowadays found in Red-capped mangabeys and Cercopithecus monkeys (i.e. Greater spot-nosed, mustached and mona monkeys: GSN, MUS, MON, respectively) and was subsequently transmitted to humans and gorillas. Nef-mediated tetherin antagonism is indicated by green and Vpu-mediated tetherin antagonism by red lines or contours, respectively. As indicated by the dashed line it is unknown whether HIV-1 group O strains originated from chimpanzees or gorillas. Photos of nonhuman primates are courtesy of M.L. Wilson, Cecile Neel and Martine Peeters