Rinaldo Lab | Department of Medicine

Welcome to the Rinaldo Laboratory

The Rinaldo laboratory studies cellular immunologic responses to human immunodeficiency virus (HIV), Kaposi’s sarcoma associated herpesvirus (KSHV or human herpesvirus 8 [HHV-8]), cytomegalovirus (CMV) and SARS-CoV-2, with the overall goal of curing and preventing these infections. The lab focus on the functions of professional antigen-presenting cells (myeloid dendritic cells, monocytes/macrophages and B lymphocytes) and their interactions with T cells. Newest areas of this research include (a) single cell transcriptomics to assess cell-to-cell transcriptome heterogeneity and cellular differences concealed by standard, bulk RNA sequencing, and (b) CRISPR/Cas9 gene-editing to target HIV-1 genome activity and immunotherapies, including T cell and natural killer cells, professional antigen presenting cells, and immune checkpoints.

Dr. Rinaldo has had continuous research grant funding from the NIH since 1979. He has mentored many graduate students and postdoctoral fellows who have advanced to prestigious positions in academia, industry and government. He is currently Principal Investigator of the NIH U01 Pitt Men’s Study, which is a clinical research site in the MACS-WIHS Combined Cohort Study, Principal Investigator of an NIH R01 grant on immune responses to COVID-19 vaccines in people with HIV (PWH), Director of an Immunology Specialty Laboratory for the NIH AIDS Clinical Trials Group, and Director of the Systems Biology & Biostatistics Core F of the Rustbelt Center for AIDS Research. These projects provide resources and biologic specimens for a broad variety of important research projects.

Charles R. Rinaldo, PhD

Contact

Charles R. Rinaldo, PhD
rinaldo@pitt.edu

Tel: 412-624-392

Laboratory:

817 Scaife Hall
3550 Terrace Street
Pittsburgh, PA 15261

Meet Our Current Lab Members

Top Row, Left to right: Dr. Yue Chen, Mr. Peter Shoucair, Dr. Charles Rinaldo, Ms. Susan Mcquiston, Ms. Abigail Gerberick

Bottom Row, Left to right: Ms. Kathy Hartle, Ms. Arlene Bullotta, Ms. Kathy Kulka, Mr. Patrick Mehta

Rinaldo Laboratory Contributions to Science

CMV infection and immunosuppression

Primary CMV infection is detectable in blood neutrophils and can cause a mononucleosis with a profound, self-limiting immunosuppression in immunocompetent adults. This research was an integral factor referenced in original CDC report on AIDS, June, 1981. CMV remains a major viral cofactor in HIV infection in current approaches to cure HIV infection.

Key publications related to this work

Rinaldo CR Jr, Black PH, Hirsch MS. Interaction of cytomegalovirus with leukocytes from patients with mononucleosis due to cytomegalovirus. J Infect Dis. 1977;136:667-678.

Levin MJ, Rinaldo CR Jr, Leary PL, Zaia JA, Hirsch MS. Immune response to herpesvirus antigens in adults with acute cytomegaloviral mononucleosis. J Infect Dis. 1979;140:851-857.

Rinaldo CR Jr, Carney WP, Richter BS, Black PH, Hirsch MS. Mechanisms of immunosuppression in cytomegaloviral mononucleosis. J Infect Dis. 1980;141:488-495.

Rinaldo CR. Cytomegalovirus: 40 years and still the major viral cofactor in HIV infection. AIDS 2022;36:1311-1313.

HIV-1 load as a predictor of AIDS

First reports to demonstrate that HIV-1 RNA levels in blood in the first year of infection can predict risk for development of AIDS 10 years later. Viral load testing remains the standard of care in management and prognosis of HIV infection.

Key publications related to this work

Mellors JW, Kingsley LA, Rinaldo CR Jr, Todd JA, Hoo BS, Kokka RP, Gupta P. Quantitation of HIV- 1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med. 1995;122:573-579.

Mellors JW, Rinaldo CR Jr, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996;272:1167-1170.

Mellors JW, Muñoz A, Giorgi JV, Margolick JB, Tassoni CJ, Gupta P, Kingsley LA, Todd JA, Saah AJ, Detels R, Phair JP, Rinaldo CR Jr. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med. 1997;126:946-954.

Mellors, JW, Margolick, JB, Phair, JP, Rinaldo, CR, Detels, R, Jacobson, LP, Munoz, A. Prognostic value of HIV-1 RNA, CD4 cell count, and CD4 Cell count slope for progression to AIDS and death in untreated HIV-1 infection. JAMA 2007; 297:2349-2350.

Myeloid dendritic cells (DC) are key to activating latent HIV-1 and inducing anti-HIV-1 T cell immunity

First comprehensive report that programmed DC expressing HIV-1 antigens are potent antigen-presenting cells (APC) and maintain strong induction of cytokines in memory CD8+ T cells during untreated PWH and those on antiretroviral drug therapy (ART). DC can prime naïve T cells to HIV-1 in PWH during ART to produce cytokines and kill HIV-1 infected cells. This research also revealed that immune checkpoint PD-1 on CD8 T cells has dual, contradictory roles in anti-HIV-1 T cell immunity, and that DC activate latent HIV-1 (the “kick”) in CD4 T cells and stimulate CTL that kill these infected cells (“the kill”). DC are being used in “kick and kill” clinical trials to control and ultimately cure HIV-1 infection.

Key publications related to this work

Macatangay BJ, Riddler SA, Wheeler ND, Spindler J, Lawani M, Hong F, Buffo MJ, Whiteside TL, Kearney MF, Mellors JW, Rinaldo, CR. Therapeutic vaccination with dendritic cells loaded with autologous HIV-1-infected apoptotic cells. J Infect Dis 2016;213:1400-1409.

Smith KN, Mailliard RB, Piazza PA, Fischer W, Korber BT, Fecek RJ, Ratner D, Gupta P, Mullins JI, Rinaldo CR. Effective cytotoxic T lymphocyte targeting of persistent HIV-1 during antiretroviral therapy requires priming of naive CD8+ T cells. mBio 2016; 7:e00473-16.

Kristoff J, Palma ML, Garcia-Bates TM, Shen C, Sluis-Cremer N, Gupta P, Rinaldo CR, Mailliard RB. Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1. EBioMed 2019; S2352-3964: 30222-1.

Garcia-Bates TM, Palma ML, Anderko RR, Hsu DC, Ananworanich J, Korber BT, Gaiha GD, Phanuphak N, Thomas R, Tovanabutra S, Walker BD, Mellors JW, Piazza PA, Kroon E, Riddler SA, Michael NL, Rinaldo CR, Mailliard RB; I4C and RV254 Study Groups. Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes. EBioMedicine. 2021;63:103175.

T cell control and DC/B cell targeting by HHV-8 (KSHV)

First reports of primary infection with HHV- 8 (KSHV), CD8+ T cell responses to HHV-8, targeting of APC by HHV-8 via DC-SIGN, and HHV-8 targeting of B cell subsets for lytic infection and poly-cytokine responses in relation to increased risk for KS.

Key publications related to this work

Rappocciolo, G., Jenkins, F.J., Hensler, H.R., Piazza, P., Jais, M., Borowski, L., Watkins, S.C., and Rinaldo, C.R., Jr. DC-SIGN is a receptor for human herpesvirus 8 on dendritic cells and macrophages. J. Immunol. 2006; 176:1741-1749.

Rappocciolo G, Hensler HR, Jais M, Reinhart TA, Pegu A, Jenkins FJ, Rinaldo CR. Human herpesvirus 8 infects and replicates in primary cultures of activated B lymphocytes through DC-SIGN. J Virol. 2008;82:4793-4806.

Knowlton ER, Rappocciolo G, Piazza P, Lepone LM, Nadgir SV, Bullotta A, Berendam SJ, Li J, Reinhart TA, Jenkins FJ, Rinaldo CR. Human herpesvirus 8 induces polyfunctional B lymphocytes that drive Kaposi’s sarcoma. mBio 2014;5:e01277-14.

Rappocciolo, G., Jais M., Piazza, P.A., DeLucia, D.C., Jenkins, F.J., Rinaldo, C.R. Human herpesvirus 8 infects and replicates in Langerhans cells and interstitial dermal dendritic cells and impairs their function. J Virol. 2017; 91:e000909-17.

HIV-1 trans infection in nonprogressors

Discovery that HIV-1 trans infection mediated by APC is restricted in nonprogressors due to a genetically inherited alteration in APC cholesterol metabolism. Novel genetic basis for the innate ability of the host to blunt HIV-1 disease progression. This opens new approaches for control of HIV-1 infection, and could have broader, non-HIV-1 clinical implications.