Selective impact of HIV disease progression on the innate immune system in the human female reproductive tract.
BACKGROUND
We have previously demonstrated intrinsic anti-HIV activity in cervicovaginal lavage (CVL) from HIV-infected women with high CD4 counts and not on antiretroviral therapy. However, the impact of HIV disease progression on CVL innate immune responses has not been delineated.


METHODS
CVL from 57 HIV-infected women not on antiretroviral therapy were collected by washing the cervicovaginal area with 10 ml of sterile normal saline. We characterized subject HIV disease progression by CD4 count strata: >500 cells/µl, 200-500 cells/µl, or <200 cells/µl of blood. To assess CVL anti-HIV activity, we incubated TZM-bl cells with HIV plus or minus CVL. Antimicrobials, cytokines, chemokines and anti-gp160 HIV IgG antibodies were measured by ELISA and Luminex.


RESULTS
CVL exhibited broad anti-HIV activity against multiple laboratory-adapted and transmitted/founder (T/F) viruses, with anti-HIV activity ranging from 0 to 100% showing wide variation between viral strains. Although there was broad CVL inhibition of most both laboratory-adapted and T/F virus strains, there was practically no inhibition of T/F strain RHPA.c, which was isolated from a woman newly infected via heterosexual intercourse. HIV disease progression, measured by declining CD4 T cell counts, resulted in a selective reduction in intrinsic anti-HIV activity in CVL that paralleled CVL decreases in human beta-defensin 2 and increases in Elafin and secretory leukocyte protease inhibitor. HIV disease progress predicted decreased CVL anti-HIV activity against both laboratory-adapted and T/F strains of HIV. Anti-HIV activity exhibited close associations with CVL levels of fourteen cytokines and chemokines.


CONCLUSIONS
Amid a multifaceted immune defense against HIV-1 and other sexually transmitted pathogens, HIV disease progression is associated with selective disturbances in both CVL anti-HIV activity and specific innate immune defenses in the human female reproductive tract (FRT). Overall, these studies indicate that innate immune protection in the FRT is compromised as women progress to AIDS.
Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America. Timothy.Lahey@Dartmouth.edu
Timothy
T
Lahey
Mimi
M
Ghosh
John V
JV
Fahey
Zheng
Z
Shen
Lucy R
LR
Mukura
Yan
Y
Song
Susan
S
Cu-Uvin
Kenneth H
KH
Mayer
Peter F
PF
Wright
John C
JC
Kappes
Christina
C
Ochsenbauer
Charles R
CR
Wira
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D018925:Chemokines / Q000276:immunology; D003075:Coitus; D003710:Demography; D018450:Disease Progression; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects / Q000276:immunology* / Q000821:virology*; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology* / Q000635:transmission / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D020010:Heterosexuality / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000187:drug effects / Q000276:immunology*; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D008875:Middle Aged; D012307:Risk Factors; D018523:Tropism / Q000187:drug effects; D044364:Vaginal Douching; D019562:Viral Load / Q000187:drug effects; D055815:Young Adult
D019380:Anti-HIV Agents; D018925:Chemokines