The presence of the Trim5alpha escape mutation H87Q in the capsid of late stage HIV-1 variants is preceded by a prolonged asymptomatic infection phase.
BACKGROUND
Recently, the tripartite interaction motif 5alpha (Trim5alpha) has been identified as an inhibitory factor blocking infection of a broad range of retroviruses in a species-specific manner. In particular, HIV-1 replication can be efficiently blocked by Trim5alpha from Old World monkeys. The cyclophilin A binding region in the HIV-1 capsid is believed to be the viral determinant for Trim5alpha, and mutations in this region lift the restriction in simian cells. Human Trim5alpha is also able to inhibit HIV-1 replication in vitro, implying that Trim5alpha may contribute to host control of HIV-1 replication in vivo.


METHODS
HIV-1 variants from participants of the Amsterdam cohort studies were analysed for Trim5alpha escape mutations in the capsid. Patients who harboured HIV-1 variants with Trim5alpha escape mutations were compared with patients who lacked such variants in terms of clinical course of infection.


RESULTS
Trim5alpha escape mutants emerged in the late phase of infection and were ultimately present in 13.7% of HIV-1 infected individuals. Patients who developed Trim5alpha escape variants late in infection had a significantly lower set-point plasma viral RNA load and concomitantly a prolonged asymptomatic survival as compared to individuals who lacked Trim5alpha escape mutants. This protective effect was stronger in individuals who later developed X4 variants. In addition, X4-emergence was delayed in individuals who later developed Trim5alpha escape variants, compatible with suppression of viral replication.


CONCLUSIONS
Our data are compatible with Trim5alpha-mediated suppression of viral replication, resulting in prolonged asymptomatic survival and ultimately the selection of Trim5alpha escape variants.
Kootstra
Neeltje A
NA
Department of Clinical Viro Immunology, Sanquin Research, Landsteiner Laboratory, University of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. N.Kootstra@sanquin.nl
Navis
Marjon
M
Beugeling
Corrine
C
van Dort
Karel A
KA
Schuitemaker
Hanneke
H
D000090103:Antiviral Restriction Factors; D002213:Capsid / Q000502:physiology; D036022:Capsid Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D009154:Mutation; D012367:RNA, Viral / Q000097:blood; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D019562:Viral Load; D014779:Virus Replication / Q000235:genetics*
D000090103:Antiviral Restriction Factors; D036022:Capsid Proteins; D002352:Carrier Proteins; D012367:RNA, Viral; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases