HIV infection en route to endogenization: two cases
Authors: J. Denner
Journal: Clinical Microbiology and Infection (2014)

I read the manuscript HIV infection en route to endogenization: two cases [[1]Colson P, Ravaux I, Tamalet C, Glazunova O, Baptiste E, Chabriere E, et al. HIV infection en route to endogenization: two cases. Clin Microbiol Infect epub ahead of print DOI: 10.1111/1469-0691.12807.Google Scholar] with great interest. The authors described two individuals infected with HIV-1, but without virus expression. The immune responses indicated that a productive infection occurred previously, but the proviruses were inactivated by mutations and the authors proposed that HIV cure may occur through HIV endogenization [[1]Colson P, Ravaux I, Tamalet C, Glazunova O, Baptiste E, Chabriere E, et al. HIV infection en route to endogenization: two cases. Clin Microbiol Infect epub ahead of print DOI: 10.1111/1469-0691.12807.Google Scholar]. I was, however, surprised to read how the terms ‘endogenization’ and ‘neutralization’, two well-defined terms in retrovirology and immunology, were used. First, in retrovirology, endogenization of a retrovirus is defined as infection of germ cells (the male sperm cell or the female oocyte) or their precursor cells with an exogenous retrovirus. As retroviruses integrate a DNA copy of their RNA genome into the genome of the target cell, eventually all cells of the organism resulting from the fusion of the infected germ cells carry this provirus, which is then termed an endogenous retrovirus. In the publication by Colson et al. [[1]Colson P, Ravaux I, Tamalet C, Glazunova O, Baptiste E, Chabriere E, et al. HIV infection en route to endogenization: two cases. Clin Microbiol Infect epub ahead of print DOI: 10.1111/1469-0691.12807.Google Scholar], human immunodeficiency virus 1 (HIV-1) is not endogenized as stated repeatedly in their publication, but merely integrated in only some of the body cells (<20 copies/106 peripheral blood mononuclear cells), as is typical for all exogenous retroviruses. Second, although one can of course neutralize an acid, one can also neutralize a virus to make it inactive, but in immunology ‘neutralization’ generally refers to the antibody-mediated prevention of virus infection. Interestingly, both case patients described have antibodies neutralizing the HIV-1 strain NL4.3. I was also surprised at the use of the term ‘cure’: this should have been termed ‘spontaneous cure’ in contrast to a cure based on treatment, e.g. with drugs. Last but not least, the spontaneous cure described was obviously due to an inactivation of HIV-1 by mutations in different regions of the viral genome. In one case vif, vpr, vpu and tat were mostly affected, in the other gag, pol, env and nef. The authors suppose a role for the cellular restriction factor APOBEC3G, an RNA editing enzyme exchanging G for A in viral nucleic acids. Usually, the viral infectivity factor (Vif) protein of HIV-1 counteracts this effect. Vif interacts with APOBEC3G and triggers the ubiquitination and degradation of APOBEC3G via the proteasomal pathway. Obviously, in one patient, vif was deactivated by mutations. The manuscript reports a very interesting mechanism of virus inactivation and certainly we can learn from this for further treatment. However, it has nothing to do with endogenization and the phenomenon should be called what it is: inactivation of the provirus in infected cells. In addition, I would like to draw your attention to the fact that endogenization of a retrovirus does not automatically mean inactivation or enslavement for placental development [[2]Denner J. Endogenous retroviruses.in: Kurth R. Bannert Retroviruses: molecular biology, genomics and pathogenesis. Caister Academic Press, Hethersett, Norwich2010: 35-69Google Scholar]. Endogenous retroviruses of mice, cats and obviously also koala are still able to contribute to tumour development and immunosuppression. Endogenous retroviruses of the pig can be released as virus particles able to infect human cells. These represent a potential risk for the use of pig cells or organs in xenotransplantation. Until now, no replication-competent human endogenous retroviruses have been found, and their inactivation reflects a long path of evolution. Nevertheless, at the moment it cannot be excluded that single proteins or insertional mutagenesis of human endogenous retroviruses contribute to tumour development in humans [[2]Denner J. Endogenous retroviruses.in: Kurth R. Bannert Retroviruses: molecular biology, genomics and pathogenesis. Caister Academic Press, Hethersett, Norwich2010: 35-69Google Scholar]. Please allow a final short sentence concerning the accompanying editorial [[3]Antonelli G. From ‘purging’ to ‘endogenization’ of the HIV genome: a new approach to HIV eradication? Editorial comment. Clin Microbiol Infect epub ahead of print DOI: 10.1111/1469-0691.12808.Google Scholar]. Modesty forbids us to accept that my laboratory demonstrated endogenization of the koala retrovirus [[4]Fiebig U. Hartmann M.G. Bannert N. Kurth R. Denner J. Transspecies transmission of the endogenous koala retrovirus (KoRV).J Virol. 2006; 80: 5651-5654Crossref PubMed Scopus (91) Google Scholar], this work was done solely by the laboratory of Paul Young [[5]Tarlington R.E. Meers J. Young P.R. Retroviral invasion of the koala genome.Nature. 2006; 442: 79-81Crossref PubMed Scopus (276) Google Scholar]. I would like to thank V. Morozov and S. Norley, Robert Koch Institute, for useful comments on the manuscript. The author declare that he has no conflicts of interest.