The major focus of the HIV-Specific Immunity Section is identifying the mechanisms of an effective humoral and cellular immune response to HIV. Identifying the components, targets, and magnitude of such responses is a critical step toward the development of effective vaccines and immunotherapies. In our investigation, we recruit patients who are the best available examples of effective humoral or cellular responses to HIV and study their immune response in detail. The knowledge provided by this work offers fundamental insights about the regulation of human immune responses to HIV and other viruses.

Mechanisms of Immunologic Restriction of HIV replication

(Stephen A. Migueles, M.D., Lead Investigator)

A number of recent studies have provided evidence for the role of CD8⁺ T cells in restricting lentivirus replication in vivo; however, the reason the CD8⁺ T-cell response fails to control HIV in the majority of infected individuals remains incompletely understood. It is now clear that there exists a group of rare patients who maintain immunologic restriction of HIV replication, despite prolonged infection, without the use of antiretroviral therapy. Many of these patients have been infected for more than 20 years with no CD4⁺ T-cell decline. These patients, referred to as long-term nonprogressors (LTNP), or “elite controllers,” likely hold important clues to the components of an effective immune response to HIV.

NIAID is recruiting volunteers for a study that will examine how the immune system controls HIV infection.

Conversely, they also hold important clues regarding how control of HIV replication is lost in most infected individuals. We have now assembled a large cohort of patients with nonprogressive infection. Cells from these patients, as well as from major histocompatibility complex (MHC) matched and mismatched progressors as controls, are being used to systematically dissect the mechanisms of immune-mediated restriction of HIV replication.

Major Findings

• Within our cohort of LTNP is a dramatic overrepresentation of the B*5701 class I allele: 68 percent compared to 11 percent in the caucasian U.S. population.
• CD8⁺ T-cell response to HIV-1 in LTNP is more narrow (typically directed toward three to four epitopes) than the response in progressors (typically 15 to 20 epitopes).
• CD8⁺ T-cell response of LTNP is highly focused on peptides restricted by the B*5701 allele, in most cases to the exclusion of peptides restricted by other alleles.
• Very high frequencies of circulating CD8⁺ T cells (0.8 to 18 percent IFN-g producing) were found to be HIV-specific in both LTNP and progressors, suggesting the difference in effectiveness of patients’ responses is qualitative rather than quantitative.
• The autologous virus is recognized by a high-frequency response in both patient groups. There are no differences between patient groups in the frequency of putative “escape mutations.”
• LTNP are distinguished by the maintenance of HIV-specific CD8⁺ T cells with a high proliferative capacity. This proliferation was found to be coupled to or parallel to perforin expression.
• HIV-specific CD4⁺ T cells in treated progressors are similar in frequency, function, and phenotype to those in LTNP and to non-HIV specific responses in uninfected controls.
• LTNP/EC are distinguished from progressors by a dramatic difference in CD8⁺ T-cell-mediated killing of HIV-infected cells. This difference in killing is mediated by the granule-exocytosis pathway through differences in perforin and granzyme B production.
• Cytotoxic killing of HIV-infected cells is a leading candidate for an immune correlate of vaccine-induced immunologic control of HIV.

Mechanisms of broad cross-neutralization of HIV

(Kenta Matsuda, Ph.D., Lead Investigator)

There is a growing consensus that eliciting both neutralizing antibodies and a potent T-cell response will be necessary for an effective HIV vaccine. Eliciting neutralizing antibodies to HIV, however, has been a challenging goal. Thus far, efforts to determine the mechanism(s) of broad cross-neutralization by patient sera have been hampered by a number of obstacles, including a lack of cohorts with broad responses, a lack of techniques to purify antigen-specific cells, and inefficient cloning techniques. Our work, along with the work of colleagues, has overcome a number of these obstacles and is permitting a careful study of specificities that mediate broad cross-neutralization. Some of the antibodies we have isolated are among the most broad and potent thus far descried and are in various stages of development by academia and biopharmaceutical companies for prophylaxis or immunotherapy. We have now begun work to attempt to stimulate similar responses by vaccination in pre-clinical experiments or early phase 1 trials.

Major Findings

• Broad cross-neutralizaiton of HIV is not rare and can be found in up to 20 percent of HIV-infected patients.
• Cloning of individual memory B cells from patients with broadly cross-neutralizing antibodies is resulting in isolation of antibodies capable of neutralizing 98 percent of tested strains.
• Broad and potent monoclonal antibodies are providing important clues regarding the best targets within the HIV envelope protein to mediate a broad neutralization of HIV. The specificities of these antibodies have very important implications for the design of vaccines against HIV-1.

Dr. Connors received his M.D. from Temple University and was trained in pediatrics at Tufts New England Medical Center. He joined the NIAID Laboratory of Infectious Diseases in 1989 to study the immune response to respiratory syncytial virus. He was trained in infectious diseases at the National Institutes of Health Clinical Center and at the Children’s Hospital of Philadelphia. He joined the Laboratory of Immunoregulation in 1994 to study the human immune response to HIV. Dr. Connors has published a series of discoveries that have laid the framework for current understanding of immunologic control of HIV in some rare patients and loss of immunologic control in the majority of infected patients.

Huang J, Kang BH, Ishida E, Zhou T, Griesman T, Sheng Z, Wu F, Doria-Rose NA, Zhang B, McKee K, O'Dell S, Chuang GY, Druz A, Georgiev IS, Schramm CA, Zheng A, Joyce MG, Asokan M, Ransier A, Darko S, Migueles SA, Bailer RT, Louder MK, Alam SM, Parks R, Kelsoe G, Von Holle T, Haynes BF, Douek DC, Hirsch V, Seaman MS, Shapiro L, Mascola JR, Kwong PD, Connors M. Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth. Immunity. 2016 Nov;45(5):1108-1121.

Migueles SA, Connors M. Success and failure of the cellular immune response against HIV-1. Nature Immunology. 2015 Jun;16(6):563-570.

Huang J, Kang BH, Pancera M, Lee JH, Tong T, Feng Y, Georgiev IS, Chuang GY, Druz A, Doria-Rose NA, Laub L, Sliepen K, van Gils MJ, de la Pena AT, Derking R, Klasse PJ, Migueles SA, Bailer RT, Alam M, Pugach P, Haynes BF, Wyatt RT, Sanders RW, Binley JM, Ward AB, Mascola JR, Kwong PD, Connors M. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface. Nature. 2014 Nov;515(7525):138-42.

Huang J, Ofek G, Laub LB, Louder M, Doria-Rose N, Longo NS, Imamichi H, Bailer R, Chakrabarti B, Sharma S, Alam M, Wang T, Yang Y, Zhang B, Migueles S, Wyatt R, Haynes B, Kwong D, Mascola J, Connors M. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature. 2012 Nov;491(7424):406-412.

Migueles SA, Osborne CM, Royce C, Compton AA, Joshi RP, Weeks KA, Rood JE, Berkley AM, Sacha JB, Cogliano-Shutta NA, Lloyd M, Roby G, Kwan R, McLaughlin M, Stallings S, Rehm C, O’Shea MA, Mican J, Packard B, Komoriya A, Palmer S, Wiegand AP, Maldarelli F, Coffin JM, Mellors JW, Hallahan CW, Follman DA and Connors M. Lytic Granule Loading of CD8+ T-Cells is Required for HIV-Infected Cell Elimination Associated with Immune Control. Immunity. 2008 Dec;29(6):1009-1021.

Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, Hallahan C, Van Baarle D, Kostense S, Miedema F, McLaughlin M, Ehler L, Metcalf J, Liu S, and Connors M. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nature Immunol. 2002 Nov;3(11):1061-1068.

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Shown is a confocal image of an HIV-specific CD8+ T cell from a long-term nonprogressor/elite controller that has been previously stimulated by an autologous HIV-infected CD4+ T cell. The nucleus is shown in blue, T-cell receptor in red, granzyme and perforin containing granules in white and green, respectively.