Can HPV, cervical neoplasia or. HIV transmission?

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1 Interactions between HPV and HIV: STIs and HIV shedding, regulation of HPV by HIV, and HPV VLP influence upon HIV Jennifer S. Smith Department of Epidemiology pd University of North Carolina

2 Can HPV, cervical neoplasia or genital warts increase Credible mechanisms (Cohen) HIV transmission? HPV, Cervical Neoplasia or Warts HIV genital tract viral burden? Disruption of tissue barriers and defenses? Increased number of cells receptive to HIV? Biological plausibility: -HIV/HPV interactions -Induction of specific anti-hiv cytokines Increased risk of HIV seroconversion?

3 STIs and HIV Shedding HIV shedding associated with genital ulcers or co-infection with other sexually transmitted infections in several studies. Relatively few data have examined associations between HPV infection, cervical neoplasia, genital warts and HIV shedding.

4 Higher HIV viral-shedding among HIV+ women co-infected with HPV Spinillo et al., Obstet Gynecol, 2001;97(6): HIV-1 seropositive women 47 paired samples of cervicovaginal lavage and blood. HIV viral load shedding ascertained -Proviral DNA -RNA transcripts -Cell-free RNA Lavage Swab

5 HIV shedding higher among women co-infected with HPV N=124 HIV+ women HPV-DNA (%) Adjusted d ORs HIV-DNA Negative <48 copies/10 5 cells (0.28, 2.31) 48 copies/10 5 cells (0.51, 2.86) HIV RNA transcripts Negative <25 copies/10 5 cells (0.51, 3.64) 25 copies/10 5 cells (1.58, 37.55) Cell-free HIV-RNA Negative <250 copies/ml (0.58, 5.93) 250 copies/ml (1.52, 36.76) Spinillo et al., Obstet Gynecol, 2001;97(6):

6 Greater HIV-1 RNA Shedding Following Treatment for CIN 2/3 Wright et al., Am J Obstet Gynecol, 2001; 184: HIV-seropositive women with CIN 2/3 Follow-up at 2, 4, 8 and 14 weeks post-treatment treatment Quantification of cell-free HIV-RNA -Cervicovaginal lavage -Cell Cllf Cell-free plasma

7 HIV Shedding Among HIV+ Women Pre- and Post- Treatment for CIN 2/3 Greatest increase in HIV genital tract virus occurred when the cervical epithelium appeared acutely inflammed. As the cervix healed after treatment (6-14 weeks), the amount of HIV viral shedding decreased. d Relatively constant HIV virus levels in plasma over study follow-up. Wright et al., Am J Obstet Gynecol, 2001; 184:

8 HIV-1 RNA Higher Following Treatment for CIN 2/3 Wright et al., Am J Obstet Gynecol, 2001; 184:

9 HIV-1 RNA Higher Following Treatment for CIN 2/3 Cervical inflammation and ulceration increased elevation of local CD4+ lymphocytes and macrophages increased number of HIV-1 infected cells that are actively replicating Were HIV infected cells from cervico-vaginal vaginal mucosae or surrounding regional lymphoid tissue? Wright et al., Am J Obstet Gynecol, 2001; 184:

10 HIV Shedding Studies: Limitations to consider Most studies are cross-sectional, with no clear direction of causality. Different laboratory methodology for ascertaining HIV shedding across studies. Potential for blood contamination. More data are needed on qualitative measures of HIV shedding, rather than odds ratios. Limited sample sizes, particularly for effect measures for cervical neoplasia, with no data available on stage of disease (e.g. CIN-1, 2/3).

11 Disruption of tissue barriers and defenses? HIV+ women with CIN and genital warts: Inflammation and increased friability of infected tissue.

12 Increased number of cells receptive to HIV? Increased lymphocyte and macrophage infiltrates among women with CIN or genital warts as compared with women with normal diagnoses.

13 What about HIV/HPV interactions?

14 HPV and HIV Protein/Protein Interactions HIV TAT AND HPV E7 Arany et al., Sex Transm Inf, 1998;74: In HIV+ individuals: Higher HIV Tat levels l correlated with higher h HPV E7 levels in biopsies of condylomas.

15 HPV and HIV Interactions Dolei et al., J Gen Virol, 1990; 80(11): HIV Tat appeared to affect HPV gene expression in cervical carcinoma cells co-cultivated cultivated with HIV-1 infected cells. HIV-1 Tat addition to culture dose dependent increase in HPV 18 E1 and L1 RNA in HPV 18 infected epithelial cells. HIV-1 may promote HPV-associated cervical carcinogenesis.

16 Does HIV Infect Epithelial Cells? Whether HIV infects cervical epithelial cells is currently debated. In vitro HPV regulation by HIV may not apply in vivo if HPV-infected epithelial cells may not be infected db by HIV.

17 Primary cervical epithelial monolayers are resistant to HIV Greenhead et al., J Virol, 2000; 74(12):

18 HIV Type 1 Infection and Replication in Normal Human Oral Keratinocytes Liu et al.,,journal of Virology, Mar. 2003,,p PCR analysis of proviral DNA constructs showed that normal lhuman oral lkeratinocytes t can be infected dby CXCR4-tropic and dualtropic (89.6) strains of HIV-1 to generate a weak kbut tproductive infection.

19 Effects of HPV-associated Cells on HIV gene expression Gage et al., Obstet Gynecol, 2000; 96(6): HPV may enhance HIV expression via production of immune and inflammatory factors. Supernatants from cervical biopsy cultures, cervical cancer cell lines, HPV immortalized keratinocytes and normal keratinocytes incorporated in cultures for cells with latent HIV from a U1 monocytic cell line. All supernatants upregulated HIV p24 expression in U1.

20 Induction of specific anti-hiv cytokines Increased concentration of proinflammatory cytokines influencing HIV replication. HIV+/HPV+ treatment-naïve women compared to HIV-/HPV+: Dually infected women had higher IL-1α and IL-1β but not TNFα. Data suggest increased immune activation and inflammation of women coinfected with HPV/HIV. Behbahani et al., J Acquired Defin Syndrome; 45 (1):9-19.

21 Effect of HPV, cervical neoplasia or genital warts on HIV seroconversion? Data are currently very limited. There are no data, to our knowledge, that report the influence of HPV persistence over time, or of clinically ascertained cervical neoplasia, on the risk of HIV acquisition.

22 Does HPV Increase the Risk of HIV Seroconversion? Smith-McCune et al., 24 th International Papillomavirus Conference & Clinical Workshop, Beijing, Nov ,040 women enrolled in RCT of female diaphragm use in Zimbabwe -Median age 28 -Median follow-up of 21 months -Pooled analysis of intervention and control arms -Baseline positivity of any HPV type increased the risk of HIV seroconversion Hazard ratio=1.6

23 Does HPV Increase the Risk of HIV seroconversion? Chin-Hong et al., 24 th International Papillomavirus Conference & Clinical Workshop, Nov ,409 men having sex with men Higher risk of HIV seroconversion observed among men HPV DNA positive at baseline, and at the time of HIV seroconversion. Hazard ratio (HR)=1.5 for each additional HPV type detected at time of HIV seroconversion. HR=3.3 for 3 or more HPV types detected.

24 Impact of Genital Warts on the Risk of Homosexual men in Brazil HIV Acquisition? Higher risk of HIV seroconversion among those with condyloma 6 months before seroconversion Risk ratio =4.3. Association not significant after controlling for age, age at first intercourse, HBV core antibody, and gonorrhea. Ref: Harrison LH et al., JAIDS. 1999; 21(5): 408.

25 Effects of HPV VLP on HIV replication HPV Virus Like Particle -Binds to Toll-like like receptors (TLR) on dendritic cells. TLR links innate immune responses against pathogens and produces anti-hiv-1 cytokines. -Induces Inducesanti-HIV cytokines (IFN-α, α IL-10, Interferonγ). Yang et al., J Virology, 2004; Garain-Pineres et al, Eur J Immunology, 2006: 36:

26 Effects of HPV VLP on HIV replication HPV-virus like particle -Strongly inhibit replication of X1 and R5 HIV-1 in peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs). -Release HIV suppressive factors ( potential antiviral genes including IL-27).

27 Impact of VLP on X4 or R5 HIV-1 Replication in PBMC Fakuruddin et al., Blood, 2007; 109:1841 X4 virus R5 virus VLP suppresses both X4 and R5 HIV-1 replication in PBMC

28 Impact of Pretreatment of PBMC with VLP on X4 HIV-1 Replication 24 hr pretreatment is sufficient for inhibition Fakuruddin et al., Blood, 2007;109:1841

29 Impact of Recombinant IL-27 on X4 HIV-1 Replication in PBMCs Fakuruddin et al., Blood, 2007; 109:1841

30 Impact of Recombinant IL-27 on X4 HIV Replication in CD4 + T cells Fakuruddin et al., Blood, 2007; 109:1841

31 Impact of Recombinant IL-27 on R5 HIV-1 Replication in MDMs Fakuruddin et al., Blood, 2007; 109:1841

32 Thus, HPV VLP induced decreases in HIV viral replication would potentially have a therapeutic effect, rather than a prophylactic effect, if confirmed in future clinical trials. Fakuruddin et al., Blood, 2007; 109:1841

33 Future Epidemiology Research Needs HPV, cervical neoplasia and genital warts on the risk of HIV shedding and plasma viral loads, addressing limitations. HIV seroconversion studies, examining the effect of HPV persistence as well as cervical neoplasia and genital warts with sufficient sample sizes. HPV vaccine effectiveness studies, examining HIV and associated outcomes.