Immunogenetic Modulators of Mucosal Protection From HIV-1

HIV Infections Clinical Trial

— Kinga  

Official title:

Immunogenetic Modulators of Mucosal Protection From HIV-1: The Kinga Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03701802
• Other study ID #: STUDY00001559
• Secondary ID: R01AI129715R01AI
• Status: Completed
• Start date: September 27, 2018
• Est. completion date: September 30, 2020

Study information

• Verified date: November 2020
• Source: University of Washington
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This is a single site, prospective, observational study that seeks to assess changes in mucosal immunity that occur as a result of HIV-1 exposure, HSV-2 infection, and/or pre-exposure prophylaxis (PrEP) usage to prevent HIV-1 acquisition. The study will collect mucosal and peripheral blood samples for a detailed analysis of longitudinal immune responses, while also obtaining samples for genetic characterization to understand how variants in CD101 and UBE2V1 may modulate host mucosal responses and HIV-1 infection risk.

Description:

A challenge to development of HIV-1 vaccines is to better understand the natural immune mechanisms for protection from HIV-1 infection. To this end, immunologists have increasingly appreciated the importance of regulatory T cells in peripheral blood that modulate the magnitude and characteristics of the host inflammatory response including against infectious diseases. The investigators have recently identified specific host genetic variants in the genes CD101 and UBE2V1 that appear to strongly predispose to HIV-1 infection risk and may act through regulatory T cells and other immunologic pathways. Most studies of individuals who are repeatedly HIV-1 exposed but remain seronegative (HESN) have focused on immunological correlates in peripheral blood rather than mucosal immune responses. However, with genital mucosal tissues being the portal of entry for heterosexually transmitted HIV-1 infection, it is critical to understand the role of immunological responses to HIV-1 that occur in the genital mucosa. A valuable model to carry out such studies is offered by evaluation of HIV-Exposed SeroNegative (HESN) individuals, particularly in the context of heterosexual sex with a stable HIV-1 infected partner e.g., HIV-1 serodiscordant couples (SDC). In order to understand how genital exposure to HIV-1 may modulate these immune pathways, HIV-1 serodiscordant couples should be compared to heterosexual partners in concordant HIV-1 negative couples (CNC) where neither partner has HIV-1. This study seeks to address this important knowledge gap by enrolling high-risk HESN with defined heterosexual HIV-1 exposures in the context of serodiscordant partnerships compared to unexposed concordant seronegative controls. The study will prospectively collect mucosal and peripheral blood samples for a detailed analysis of longitudinal immune responses, while also obtaining samples for genetic characterization to understand how variants in CD101 and UBE2V1 may modulate host mucosal responses and HIV-1 infection risk.

Primary Objectives:

• To identify mucosal immunoregulatory mechanisms mediating host response to heterosexual exposure to HIV-1.

• To determine how high priority variants in CD101 and UBE2V1 modify host mucosal responses in HIV-1 exposure and infection.

Secondary Objectives:

• Identify factors (including HIV-1 exposure, host genetic and microbiota) that modify immunoregulatory mechanisms mediating host response to HIV-1

• Evaluate how these immunogenetic regulatory mechanisms influence other infectious and immunological outcomes

• Evaluate the effect of PrEP on early HIV-1 disease

Recruitment information / eligibility

• Status: Completed
• Enrollment: 812
• Est. completion date: September 30, 2020
• Est. primary completion date: September 30, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion criteria:

HIV-1 Uninfected Participants;

• Age =18 and =65 and able to provide independent informed consent for research per local regulations and guidelines

• Able and willing to provide written informed consent to be screened for and to take part in the study

• Part of a heterosexual couple in which either one or both partners meet the study eligibility criteria for partner (HIV-1 uninfected) participants. Couples are defined by the following criteria:

• Partners are sexually active (defined as having had vaginal intercourse with the enrolled partner at least 6 times in the last three months)

• Partners plan to remain in the relationship for the duration of the study period.

• HIV-1 uninfected status is based on parallel negative HIV-1 rapid tests, both at study screening and at the enrollment visit

• Able and willing to provide adequate locator information for study retention purposes, as defined by local standard operating procedures

HIV-1 Infected Participants;

• Of legal age to provide independent informed consent for research per local regulations and guidelines.

• Able and willing to provide written informed consent to be screened for and to take part in the study.

• Part of a heterosexual couple in which one partner meets the study eligibility criteria for index (HIV-1 infected) participants and the other partner meets the study eligibility criteria for partner (HIV-1 uninfected) participants

• Current or previous use of antiretroviral therapy with unsuppressed HIV-1 viral load

• HIV-1 infected based on positive EIA and, when available, detectable viral load.

• No history of any clinical AIDS-defining diagnoses.

• Able and willing to provide adequate locator information for study retention purposes, as defined by local standard operating procedures.

Exclusion criteria:

HIV-1 Uninfected Participants;

• Abnormal serum creatinine (based on sub-Saharan African normal values)

• Active and serious infections, including active tuberculosis infection or osteomyelitis and all infections requiring parenteral antibiotic therapy; active clinically significant medical problems including cardiac disease, pulmonary disease, diabetes requiring hypoglycemic medication; and previously diagnosed malignancy expected to require further treatment.

• Receiving ongoing therapy with any of the following at the time of enrollment:

antiretroviral therapy (ART), including nucleoside analogs, nonnucleoside reverse transcriptase inhibitors, protease inhibitors or investigational antiretroviral agents, interferon (alpha, beta, or gamma) or interleukin (e.g., IL-2) therapy, metformin, aminoglycoside antibiotics, amphotericin B, cidofovir, systemic chemotherapeutic agents, other agents with significant nephrotoxic potential, other agents that may inhibit or compete for elimination via active renal tubular secretion (e.g., probenecid), and/or other investigational agent

• At enrollment, has any other condition that, based on the opinion of the investigator or designee, would preclude provision of informed consent; make participation in the study unsafe; complicate interpretation of study outcome data)

• Pregnant at the time of screening

HIV-1 Infected Participants;

• Current or previous use of antiretroviral therapy with suppressed HIV-1 viral load

• Currently enrolled in another HIV-1 treatment trial

• At enrollment, has any other condition that, based on the opinion of the investigator or designee, would preclude provision of informed consent; make participation in the study unsafe; complicate interpretation of study outcome data; or otherwise interfere with achieving the study objectives.

• Pregnant at the time of screening

Related Conditions & MeSH terms

• Communicable Diseases
• HIV Infections
• HSV-2 Infection
• Infection

Locations

Country	Name	City	State
Kenya	Partners in Health, Research and Development	Thika

Sponsors (3)

Lead Sponsor	Collaborator
University of Washington	Kenya Medical Research Institute, National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

Kenya, 

References & Publications (12)

Alimonti JB, Koesters SA, Kimani J, Matu L, Wachihi C, Plummer FA, Fowke KR. CD4+ T cell responses in HIV-exposed seronegative women are qualitatively distinct from those in HIV-infected women. J Infect Dis. 2005 Jan 1;191(1):20-4. Epub 2004 Dec 1. — View Citation

Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW, Bukusi EA, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, Farquhar C, John-Stewart G, Kakia A, Odoyo J, Mucunguzi A, Nakku-Joloba E, Twesigye R, Ngure K, Apaka C, Tamooh H, Gabona F, Mujugira A, Panteleeff D, Thomas KK, Kidoguchi L, Krows M, Revall J, Morrison S, Haugen H, Emmanuel-Ogier M, Ondrejcek L, Coombs RW, Frenkel L, Hendrix C, Bumpus NN, Bangsberg D, Haberer JE, Stevens WS, Lingappa JR, Celum C; Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012 Aug 2;367(5):399-410. doi: 10.1056/NEJMoa1108524. Epub 2012 Jul 11. — View Citation

Biasin M, Piacentini L, Lo Caputo S, Naddeo V, Pierotti P, Borelli M, Trabattoni D, Mazzotta F, Shearer GM, Clerici M. TLR activation pathways in HIV-1-exposed seronegative individuals. J Immunol. 2010 Mar 1;184(5):2710-7. doi: 10.4049/jimmunol.0902463. Epub 2010 Feb 1. — View Citation

Eichhorn EJ, Tandon PK, DiBianco R, Timmis GC, Fenster PE, Shannon J, Packer M. Clinical and prognostic significance of serum magnesium concentration in patients with severe chronic congestive heart failure: the PROMISE Study. J Am Coll Cardiol. 1993 Mar 1;21(3):634-40. — View Citation

Hughes JP, Baeten JM, Lingappa JR, Magaret AS, Wald A, de Bruyn G, Kiarie J, Inambao M, Kilembe W, Farquhar C, Celum C; Partners in Prevention HSV/HIV Transmission Study Team. Determinants of per-coital-act HIV-1 infectivity among African HIV-1-serodiscordant couples. J Infect Dis. 2012 Feb 1;205(3):358-65. doi: 10.1093/infdis/jir747. Epub 2012 Jan 11. — View Citation

Lund JM, Broliden K, Pyra MN, Thomas KK, Donnell D, Irungu E, Muwonge TR, Mugo N, Manohar M, Jansson M, Mackelprang R, Marzinke MA, Baeten JM, Lingappa JR. HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis. J Virol. 2016 Oct 14;90(21):9855-9861. doi: 10.1128/JVI.01482-16. Print 2016 Nov 1. Erratum in: J Virol. 2017 Jan 18;91(3):. — View Citation

Mackelprang RD, Baeten JM, Donnell D, Celum C, Farquhar C, de Bruyn G, Essex M, McElrath MJ, Nakku-Joloba E, Lingappa JR; Partners in Prevention HSV/HIV Transmission Study Team. Quantifying ongoing HIV-1 exposure in HIV-1-serodiscordant couples to identify individuals with potential host resistance to HIV-1. J Infect Dis. 2012 Oct;206(8):1299-308. Epub 2012 Aug 27. — View Citation

Mackelprang RD, Bamshad MJ, Chong JX, Hou X, Buckingham KJ, Shively K, deBruyn G, Mugo NR, Mullins JI, McElrath MJ, Baeten JM, Celum C, Emond MJ, Lingappa JR; Partners in Prevention HSV/HIV Transmission Study and the Partners PrEP Study Teams. Whole genome sequencing of extreme phenotypes identifies variants in CD101 and UBE2V1 associated with increased risk of sexually acquired HIV-1. PLoS Pathog. 2017 Nov 6;13(11):e1006703. doi: 10.1371/journal.ppat.1006703. eCollection 2017 Nov. Erratum in: PLoS Pathog. 2019 Feb 11;15(2):e1007588. — View Citation

Pattacini L, Baeten JM, Thomas KK, Fluharty TR, Murnane PM, Donnell D, Bukusi E, Ronald A, Mugo N, Lingappa JR, Celum C, McElrath MJ, Lund JM; Partners PrEP Study Team. Regulatory T-Cell Activity But Not Conventional HIV-Specific T-Cell Responses Are Associated With Protection From HIV-1 Infection. J Acquir Immune Defic Syndr. 2016 Jun 1;72(2):119-28. doi: 10.1097/QAI.0000000000000919. — View Citation

Pattacini L, Murnane PM, Baeten JM, Fluharty TR, Thomas KK, Bukusi E, Katabira E, Mugo N, Donnell D, Lingappa JR, Celum C, Marzinke M, McElrath MJ, Lund JM; Partners PrEP Study Team. Antiretroviral Pre-Exposure Prophylaxis Does Not Enhance Immune Responses to HIV in Exposed but Uninfected Persons. J Infect Dis. 2015 Jun 15;211(12):1943-52. doi: 10.1093/infdis/jiu815. Epub 2014 Dec 17. — View Citation

Pattacini L, Murnane PM, Kahle EM, Bolton MJ, Delrow JJ, Lingappa JR, Katabira E, Donnell D, McElrath MJ, Baeten JM, Lund JM. Differential regulatory T cell activity in HIV type 1-exposed seronegative individuals. AIDS Res Hum Retroviruses. 2013 Oct;29(10):1321-9. doi: 10.1089/AID.2013.0075. Epub 2013 Jul 30. — View Citation

Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: a meta-analysis. J Infect Dis. 2002 Jan 1;185(1):45-52. Epub 2001 Dec 14. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Prevalence of genital-tract tissue resident memory (TRM) cells	We will compare frequency of CD69+ among CD8+ TRM in genital tissues between HIV-1 exposed and HIV-1 unexposed individuals	At enrollment
Other	Prevalence of genital-tract tissue resident memory (TRM) cells in individuals with versus without CD101 immunoglobulin-like (Ig-like) variants.	We will compare frequency of CD69+ among CD8+ TRM in genital tissues in individuals with versus without CD101 immunoglobulin-like (Ig-like) variants.	At enrollment
Primary	Prevalence of genital-tract tissue resident memory (TRM) cells	We will compare frequency of CD69+ among CD8+ TRM in genital tissues between HIV-1 exposed and HIV-1 unexposed individuals	At 6 months of follow-up
Secondary	Prevalence of genital-tract tissue resident memory (TRM) cells in individuals with versus without CD101 immunoglobulin-like (Ig-like) variants.	We will compare frequency of CD69+ among CD8+ TRM in genital tissues in individuals with versus without CD101 immunoglobulin-like (Ig-like) variants.	At 6 months of follow-up

External Links

•   Mackelprang et. al. ftPiPHHTaPP. Rare host genetic variation influencing risk of heterosexual HIV-1 acquisition. Congress on Retroviruses and Opportunistic Infections (CROI - 2016)