Trans-activation, post-transcriptional maturation, and induction of antibodies to HERV-K (HML-2) envelope transmembrane protein in HIV-1 infection.
BACKGROUND
Human Endogenous Retroviruses (HERVs) comprise about 8% of the human genome and have lost their ability to replicate or to produce infectious particles after having accumulated mutations over time. We assessed the kinetics of expression of HERV-K (HML-2) Envelope mRNA transcript and surface unit (SU) and transmembrane (TM) subunit proteins during HIV-1 infection. We also mapped the specificity of the humoral response to HERV-K (HML-2) Envelope protein in HIV-1 infected subjects at different stages of disease, and correlated the response with plasma viral load.


RESULTS
We found that HIV-1 modified HERV-K (HML-2) Env mRNA expression, resulting in the expression of a fully N-glycosylated HERV-K (HML-2) envelope protein on the cell surface. Serological mapping of HERV-K (HML-2) envelope protein linear epitopes revealed two major immunogenic domains, one on SU and another on the ectodomain of TM. The titers of HERV-K (HML-2) TM antibodies were dramatically increased in HIV-1 infected subjects (p < 0.0001). HIV-1 infected adults who control HIV-1 in the absence of therapy ("elite" controllers) had a higher titer response against TM compared to antiretroviral-treated adults (p < 0.0001) and uninfected adults (p < 0.0001).


CONCLUSIONS
These data collectively suggest that HIV-1 infection induces fully glycosylated HERV-K (HML-2) envelope TM protein to which antibodies are induced. These anti-HERV-K (HML-2) TM antibodies are a potential marker of HIV-1 infection, and are at higher titer in elite controllers. HERV-K (HML-2) envelope TM protein may be a new therapeutic target in HIV-1 infection.
Henri-Alexandre
HA
Michaud
Miguel
M
de Mulder
Devi
D
SenGupta
Steven G
SG
Deeks
Jeffrey N
JN
Martin
Christopher D
CD
Pilcher
Frederick M
FM
Hecht
Jonah B
JB
Sacha
Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, USA. dnixon@gwu.edu.
Douglas F
DF
Nixon
D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D020077:Endogenous Retroviruses / Q000276:immunology / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D008297:Male; D011499:Protein Processing, Post-Translational; D014759:Viral Envelope Proteins / Q000096:biosynthesis* / Q000276:immunology*; D014775:Virus Activation
D000914:Antibodies, Viral; D014759:Viral Envelope Proteins