Functional characteristics of HIV-1 subtype C compatible with increased heterosexual transmissibility.
BACKGROUND
Despite the existence of over 50 subtypes and circulating recombinant forms of HIV-1, subtype C dominates the heterosexual pandemic causing approximately 56% of all infections.


OBJECTIVE
To evaluate whether viral genetic factors may contribute to the observed subtype-C predominance.


METHODS
Chimeric viruses were generated using V1-V3 envelope fragments from a subtype-A/C dually infected woman with preferential genital replication of subtype C. Viral adaptation, spread and cell fusion ability were evaluated in vitro using peripheral blood mononuclear cells and HeLa-CD4-CCR5 cell lines, sequencing and cloning. Structural modeling was performed using a crystal structure of gp120-CD4-X5. Phylogenetic analysis was done using subtype-A, subtype-B and subtype-C sequences from blood and cervix of 37 infected women and database sequences.


RESULTS
We identified two envelope motifs, compact V1-V2 loops and V3-316T, which are found at high frequency throughout subtype-C evolution and affect gp120 interactions with CD4 and CCR5, respectively. When a V1-Delta5 deletion or V3-A316T was incorporated into subtype A, each increased viral fusion and spread several fold in peripheral blood mononuclear cell and cell lines with low CCR5 expression. Structural modeling suggested the formation of an additional hydrogen bond between V3 and CCR5. Moreover, we found preferential selection of HIV with 316T and/or extremely short V1-V2 loops in cervices of three women infected with subtypes A/C, B or C.


CONCLUSIONS
As CD4-CCR5-T cells are key targets for genital HIV infection and cervical selection can favor compact V1-V2 loops and 316T, which increase viral infectivity, we propose that these conserved subtype-C motifs may contribute to transmission and spread of this subtype.
Walter
Brandon L
BL
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
Armitage
Andrew E
AE
Graham
Stephen C
SC
de Oliveira
Tulio
T
Skinhøj
Peter
P
Jones
E Yvonne
EY
Stuart
David I
DI
McMichael
Andrew J
AJ
Chesebro
Bruce
B
Iversen
Astrid Kn
AK
D015704:CD4 Antigens / Q000235:genetics* / Q000378:metabolism; D002584:Cervix Uteri / Q000821:virology*; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000235:genetics* / Q000635:transmission / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D020010:Heterosexuality; D006801:Humans; D007150:Immunohistochemistry; D017421:Sequence Analysis; D015229:Sexually Transmitted Diseases, Viral; D014779:Virus Replication / Q000235:genetics*
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120