Human immunodeficiency virus and human papilloma virus - why HPV-induced lesions do not spontaneously resolve and why therapeutic vaccination can be successful

HIV and HPV can both cause chronic infections and are acquired during sexual contact. HIV infection results in a progressive loss of CD4+ T cells that is associated with an increased prevalence of HPV infections, type-specific persistence and an increase in HPV-associated malignancies. On the one hand this illustrates the important role of HPV-specific CD4+ helper T-cell immunity, on the other it shows the Achilles heel of the HPV-specific immune response. The use of highly active antiretroviral therapy (HAART) results in a rapid reduction of HIV and a reconstitution of systemic CD4+ T-cell levels. The use of HAART thus has the potential to raise immunity to HPV but to the surprise of many, the incidence of HPV-induced diseases has increased rather than declined since the introduction of HAART. Here, the knowledge on how HPV-induced diseases develop in the face of a non-compromised immune system will be used to explain why the effect of HAART on HPV-induced diseases is modest at best. Furthermore, exciting new data in the field of therapeutic vaccines against HPV will be discussed as this may form a more durable and clinically successful therapeutic approach for the treatment of HPV-induced high-grade lesions in HIV-positive subjects on HAART

Oncogenic Effects of HIV-1 Proteins, Mechanisms Behind

Funding Information: Funding: This study was supported the Russian Fund for Basic Research grants 17_54_30002 and 20‐04‐01034 to M.I., Latvian Science Council grants LZP‐2018/2‐0308 and LZP‐2020/2‐0376 to M.I., Funding Information: and NCI R01CA 217715 to J.P.The work of Francesca Chiodi is supported by a grant from the Swe‐ dish Medical Research Council (Francesca Chiodi; Vetenskapsrådet 2019‐01169). Publisher Copyright: © 2021 by the authors.People living with human immunodeficiency virus (HIV-1) are at increased risk of developing cancer, such as Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), cervical cancer, and other cancers associated with chronic viral infections. Traditionally, this is linked to HIV-1-induced immune suppression with depletion of CD4+ T-helper cells, exhaustion of lymphopoiesis and lymphocyte dysfunction. However, the long-term successful implementation of antiretroviral therapy (ART) with an early start did not preclude the oncological complications, implying that HIV-1 and its antigens are directly involved in carcinogenesis and may exert their effects on the background of restored immune system even when present at extremely low levels. Experimental data indicate that HIV-1 virions and single viral antigens can enter a wide variety of cells, including epithelial. This review is focused on the effects of five viral proteins: envelope protein gp120, accessory protein negative factor Nef, matrix protein p17, transactivator of transcription Tat and reverse transcriptase RT. Gp120, Nef, p17, Tat, and RT cause oxidative stress, can be released from HIV-1-infected cells and are oncogenic. All five are in a position to affect “innocent” bystander cells, specifically, to cause the propagation of (pre)existing malignant and malignant transformation of normal epithelial cells, giving grounds to the direct carcinogenic effects of HIV-1.Peer reviewe

Risk of Cancer among Commercially Insured HIV-Infected Adults on Antiretroviral Therapy.

The objective of this study was to explore the cancer incidence rates among HIV-infected persons with commercial insurance who were on antiretroviral therapy and compare them with those rates in the general population. Paid health insurance claims for 63,221 individuals 18 years or older, with at least one claim with a diagnostic code for HIV and at least one filled prescription for an antiretroviral medication between January 1, 2006, and September 30, 2012, were obtained from the LifeLink® Health Plan Claims Database. The expected number of cancer cases in the general population for each gender-age group (<30, 30-39, 40-49, 50-59, and >60 years) was estimated using incidence rates from the Surveillance Epidemiology and End Results (SEER) program. Standardized incidence ratios (SIRs) were estimated using their 95% confidence intervals (CIs). Compared to the general population, incidence rates for HIV-infected adults were elevated (SIR, 95% CI) for Kaposi sarcoma (46.08; 38.74-48.94), non-Hodgkin lymphoma (4.22; 3.63-4.45), Hodgkin lymphoma (9.83; 7.45-10.84), and anal cancer (30.54; 25.62-32.46) and lower for colorectal cancer (0.69; 0.52-0.76), lung cancer (0.70; 0.54, 0.77), and prostate cancer (0.54; 0.45-0.58). Commercially insured, treated HIV-infected adults had elevated rates for infection-related cancers, but not for common non-AIDS defining cancers

Detection and quantitation of HPV in genital and oral tissues and fluids by real time PCR

<p>Abstract</p> <p>Background</p> <p>Human papillomaviruses (HPVs) remain a serious world health problem due to their association with anogenital/oral cancers and warts. While over 100 HPV types have been identified, a subset is associated with malignancy. HPV16 and 18 are the most prevalent oncogenic types, while HPV6 and 11 are most commonly responsible for anogenital warts. While other quantitative PCR (qPCR) assays detect oncogenic HPV, there is no single tube assay distinguishing the most frequent oncogenic types and the most common types found in warts.</p> <p>Results</p> <p>A Sybr Green-based qPCR assay was developed utilizing degenerate primers to the highly conserved HPV E1 theoretically detecting any HPV type. A single tube multiplex qPCR assay was also developed using type-specific primer pairs and TaqMan probes that allowed for detection and quantitation of HPV6,11,16,18. Each HPV type was detected over a range from 2 × 10¹to 2 × 10⁶copies/reaction providing a reliable method of quantitating type-specific HPV in 140 anogenital/cutaneous/oral benign and malignant specimens. 35 oncogenic and low risk alpha genus HPV types were detected. Concordance was detected in previously typed specimens. Comparisons to the gold standard detected an overall sensitivity of 89% (95% CI: 77% - 96%) and specificity of 90% (95%CI: 52% - 98%).</p> <p>Conclusion</p> <p>There was good agreement between the ability of the qPCR assays described here to identify HPV types in malignancies previously typed using standard methods. These novel qPCR assays will allow rapid detection and quantitation of HPVs to assess their role in viral pathogenesis.</p

Validation of a Diagnostic Microarray for Human Papillomavirus: Coverage of 102 Genotypes

Papillomaviruses have been implicated in a variety of human diseases ranging from common warts to invasive carcinoma of the anogenital mucosa. Existing assays for genotyping human papillomavirus are restricted to a small number of types. Here, we present a comprehensive, accurate microarray strategy for detection and genotyping of 102 human papillomavirus types and validate its use in a panel of 91 anal swabs. This array has equal performance to traditional dot blot analysis with the benefits of added genotype coverage and the ability to calibrate readout over a range of sensitivity or specificity values

HPV vaccination of immunocompromised hosts

It is well-established that immunocompromised people are at increased risk of HPV-related disease compared with those who are immunocompetent. Prophylactic HPV sub-unit vaccines are safe and immunogenic in immunocompromised people and it is strongly recommended that vaccination occur according to national guidelines. When delivered to immunocompromised populations, HPV vaccines should be given as a 3-dose regimen

Implementation of and Early Outcomes From Anal Cancer Screening at a Community-Engaged Health Care Facility Providing Care to Nigerian Men Who Have Sex With Men.

PurposeAnal cancer risk is substantially higher among HIV-infected men who have sex with men (MSM) as compared with other reproductive-age adults, but screening is rare across sub-Saharan Africa. We report the use of high-resolution anoscopy (HRA) as a first-line screening tool and the resulting early outcomes among MSM in Abuja, Nigeria.MethodsFrom August 2016 to August 2017, 424 MSM enrolled in an anal cancer screening substudy of TRUST/RV368, a combined HIV prevention and treatment cohort. HRA-directed biopsies were diagnosed by histology, and ablative treatment was offered for high-grade squamous intraepithelial lesions (HSIL). HRA proficiency was assessed by evaluating the detection of squamous intraepithelial lesions (SIL) over time and the proportion biopsied. Prevalence estimates of low-grade squamous intraepithelial lesions and HSIL with 95% CIs were calculated. Multinomial logistic regression was used to identify those at the highest risk of SIL.ResultsMedian age was 25 years (interquartile range [IQR], 22-29), median time since sexual debut was 8 years (IQR, 4-12), and 59% (95% CI, 54.2% to 63.6%) were HIV infected. Rate of detection of any SIL stabilized after 200 screenings, and less than 20% had two or more biopsies. Preliminary prevalence estimates of low-grade squamous intraepithelial lesions and HSIL were 50.0% (95% CI, 44.7% to 55.3%) and 6.3% (95% CI, 4.0% to 9.3%). HIV infection, at least 8 years since anal coital debut, concurrency, and external warts were independently statistically associated with SIL.ConclusionProficiency with HRA increased with experience over time. However, HSIL detection rates were low, potentially affected by obstructed views from internal warts and low biopsy rates, highlighting the need for ongoing evaluation and mentoring to validate this finding. HRA is a feasible first-line screening tool at an MSM-friendly health care facility. Years since anal coital debut and external warts could prioritize screening

Gay and Bisexual Men's Willingness to Receive Anal Papanicolaou Testing

Objectives. We assessed the willingness of gay and bisexual men, who have high rates of anal cancer that might be prevented through regular screening, to receive anal Papanicolaou tests

Association of antiretroviral therapy with anal high-risk human papillomavirus, anal intraepithelial neoplasia, and anal cancer in people living with HIV: a systematic review and meta-analysis.

BACKGROUND: The effect of antiretroviral therapy (ART) on the natural history of anal high-risk HPV and anal lesion progression is not well established. We reviewed the association of ART and other HIV-related factors on anal HPV infection, anal intraepithelial neoplasia (AIN), and anal cancer among people living with HIV. METHODS: For this systematic review and meta-analysis, we searched MEDLINE and EMBASE for studies published between Jan 1, 1996, and Oct 30, 2019, that reported the association of HIV-related exposures (ART or highly active ART [HAART], HIV-RNA plasma viral load [PVL], and nadir or current CD4 cell count) with outcomes of anal high-risk HPV prevalence, incidence, and persistence; prevalence, incidence, progression, or regression of anal histological and cytological abnormalities; and anal cancer incidence. Effect estimates were extracted whenever available; otherwise, they were calculated from raw data. We assessed the risk of bias of included studies using the Newcastle-Ottawa scale, and random-effects meta-analyses were done to examine heterogeneity using the I2 statistic. This study is registered on the PROSPERO database, CRD42018007271. FINDINGS: We identified 6777 studies, of which 5377 were excluded before full-text review. 122 studies providing estimates for 130 distinct populations matched the inclusion criteria. The populations comprised 417 006 people living with HIV (women, men who have sex with men, and men who have sex with women). 41 (32%) population estimates were not stratified by sex or sexual orientation. People living with HIV receiving ART had 35% lower high-risk HPV prevalence than ART-naive people (crude odds ratio [OR] 0·65, 95% CI 0·54-0·79; I2 12·1%, p=0·31) in 18 studies, and prolonged ART use was associated with a 10% reduction per year in high-risk HPV prevalence in two studies (adjusted OR 0·90, 0·85-0·95; I2 0%, p=0·88). People living with HIV with undetectable PVL had lower HSIL-AIN2+ prevalence than those with detectable PVL (crude OR 0·84, 0·72-0·98; I2 0%, p=0·80) in 16 studies, particularly if sustained for more than 1 year (crude OR 0·62, 0·47-0·81; I2 0%, p=0·51). ART was not associated with anal cancer incidence when adjusted for years living with HIV in three studies (adjusted hazard ratio [HR] 1·11, 95% CI 0·68-1·80; I2 0%, p=0·57), but ART users with sustained undetectable HIV PVL had 44% lower risk of anal cancer than those without (adjusted HR 0·56, 0·44-0·70; I2 0%, p=0·94) and for each increase in nadir CD4 cell counts of 100 cells per μL, there was a 40% decrease in anal cancer incidence (crude HR 0·60, 0·46-0·78; I2 21·7%, p=0·26). INTERPRETATION: Effective ART use and early initiation at high nadir CD4 counts might reduce anal high-risk HPV infection and anal cancer risk. Although most studies were cross-sectional in design and few adjusted for potential confounders, this analysis provides comprehensive estimates of the effect of ART and HIV-related factors on the natural history of anal HPV-related disease in people living with HIV. FUNDING: EU Marie Skłodowska-Curie Actions programme