Long-term survivors of HIV-1 infection — whose most stringent members are now called elite controllers — maintain undetectable or very low plasma viremia and stable CD4+ T-cell counts for a decade or more without antiretroviral therapy, yet a complete mechanistic account of this spontaneous control is still lacking. The original characterization of the Aaron Diamond cohort of ten long-term survivors (Cao et al., 1995) left several issues open, of which two survive as a precise open core: the molecular identity of the CD8+ T-cell non-cytolytic antiviral activity (CAF/CNAR), a soluble activity that blocks HIV-1 transcription without killing infected cells; and the causal decomposition of durable control into host immune responses (CD8+ T-cell activity, neutralizing antibodies, HLA class I genetics) versus viral attenuation and reservoir configuration. Three decades of follow-up — beta-chemokine biology, the retracted alpha-defensin claim, HLA association studies, and near-full-length proviral sequencing of elite-controller reservoirs — have sharply refined both questions without closing either. The problem is to identify the CAF effector molecule(s) and to explain, at the level of individual patients, why drug-free control is maintained.

Background

In most people infected with HIV-1, untreated infection leads to progressive loss of CD4+ T cells and clinical AIDS within about ten years of seroconversion. A small minority — roughly 0.5% of infected people, called elite controllers, the modern term for the stringent end of the spectrum that also includes 'long-term survivors' and 'long-term nonprogressors' — remain asymptomatic with normal CD4+ T-cell counts and undetectable or very low plasma HIV-1 RNA for many years without antiretroviral therapy. Because therapeutically inducing this drug-free control is a major stated objective of HIV cure research, understanding what these rare individuals do differently is a central question of HIV immunology.

The cohort study that frames this problem (Cao, Qin, Zhang, Safrit and Ho, published as an article in the New England Journal of Medicine in 1995 and as a chapter in the Karger volume 'Global Challenge of AIDS') characterized ten long-term survivors infected for 12–15 years. It found extraordinarily low viral burdens, no detectable infectious virus in six of the ten subjects, a vigorous CD8+ T-cell response that inhibited HIV-1 replication in vitro without killing infected cells, strong neutralizing antibodies (antibodies that block viral infectivity), and replication kinetics consistent with substantially attenuated virus in two subjects. The CD8+ finding built on the discovery by Walker, Moody, Stites and Levy (1986) that CD8+ T lymphocytes from certain infected individuals suppress HIV replication through a non-cytotoxic activity, later termed the CD8+ T-cell non-cytotoxic antiviral response (CNAR) and attributed, at least in part, to a secreted CD8+ cell antiviral factor (CAF). CNAR/CAF is unusual: it is not HLA-restricted (it does not depend on recognition of viral peptides presented by HLA class I molecules — human leukocyte antigens, the cell-surface proteins that display viral peptides to CD8+ T cells), it is not epitope-specific, and it acts after infection by blocking transcription from the HIV-1 long terminal repeat (LTR, the regulatory region at each end of the integrated viral genome that contains enhancer and promoter binding sites for host transcription factors such as NF-kB and Sp1). The best-characterized CD8+-derived HIV-suppressive factors, the beta-chemokines RANTES, MIP-1alpha and MIP-1beta identified by Cocchi et al. in 1995, block entry of CCR5-tropic strains (viral strains that enter cells through the CCR5 co-receptor) and do not account for CAF, which also suppresses CXCR4-tropic virus (strains entering through the CXCR4 co-receptor) at the transcriptional level. A later claim that alpha-defensins (antimicrobial peptides made by neutrophils and some T cells) constitute CAF was retracted in 2004, and as late as the 2021 review by Levy's group the effector's identity remained unknown.

On the viral side, the same cohort was analyzed gene by gene: nef (an accessory virulence gene), the LTR, gag and pol were sequenced, and no single common genetic defect was found — only one individual carried a proviral population devastated by G-to-A hypermutation (a mutational pattern inflicted by APOBEC-family host antiviral enzymes, which chemically alter viral DNA during replication) in the LTR and in p17 gag (the segment of the gag gene encoding the viral matrix protein). Independently, the Sydney Blood Bank Cohort, infected from a single donor with a virus carrying a deletion spanning nef and the LTR, established that grossly attenuated virus can cause long-term nonprogression — but also, from 14–18 years of follow-up, that such attenuation does not guarantee lifelong protection: the donor's CD4 count declined and antiretroviral therapy was started in 1999. On the host side, genome-wide association studies (Fellay et al. 2007; the International HIV Controllers Study, Pereyra et al. 2010) showed that the strongest host genetic determinants of spontaneous control act through HLA class I peptide presentation, pointing at CD8+ T-cell pressure as a dominant force.

The modern era brought single-genome, near-full-length proviral sequencing (a provirus is the integrated DNA form of the retrovirus in a host cell; an 'intact' provirus has no lethal defects and may be replication-competent). Jiang et al. (2020) showed that elite controllers do harbor oligoclonal clusters of intact proviruses (clusters descended from a few expanded infected cell clones), but preferentially integrated in heterochromatin — tightly packed, transcriptionally silent chromatin such as centromeric satellite DNA and regions encoding KRAB-zinc-finger proteins (a large family of gene-silencing DNA-binding proteins) — where viral transcription is silenced, and that replication-competent virus can be present yet controlled in a controller carrying the HLA-B*57 class I allele (Veenhuis et al. 2018). Yet the newest reviews (Mastrangelo et al. 2022; Noel and Lambotte 2026) emphasize that elite controllers are markedly heterogeneous, that the mechanisms of control are 'not completely elucidated', and that no analysis predicts which controllers will maintain control and which will lose it (Gasca-Capote et al. 2024). The unresolved target is therefore twofold: the molecular identity and mode of action of CAF/CNAR, and a causal, individual-level account of durable control — the relative contributions of host immune responses versus viral attenuation and reservoir configuration — including why control sometimes fails.

Problem Statement

What maintains durable, drug-free control of HIV-1 in long-term survivors (elite controllers), and what are the relative contributions of host immune responses versus viral attenuation? Building on the unresolved issues raised by the original cohort characterization (Cao et al., 1995) — whose gene-by-gene viral genetics, cohort-level generality, and reservoir composition have since been substantially clarified — the surviving open problem has two linked components:

(1) Molecular identification of the CD8+ T-cell non-cytolytic antiviral activity (CNAR/CAF): which molecule or combination of molecules, secreted by CD8+ T cells of controllers, mediates the non-cytotoxic, non-HLA-restricted suppression of HIV-1 replication that acts by blocking transcription from the viral long terminal repeat (including against CXCR4-tropic strains, beyond the entry-blocking beta-chemokines), and through what effector pathway does it act?

(2) Causal decomposition of durable control: what are the relative contributions of host immune responses (CD8+ T-cell cytolytic and non-cytolytic activity, neutralizing antibodies, HLA class I genetics) versus viral attenuation and reservoir configuration (hypermutated or deleted defective proviruses, nef/LTR-deleted virus, intact-but-silenced proviruses in heterochromatin) to the aviremic state of an individual controller?

The two components are scientifically linked: the CD8+ non-cytolytic activity is one of the host effectors whose weight must be measured in the decomposition, and the answer must jointly explain the full spectrum of controller phenotypes, from rare individuals with no detectable intact provirus to controllers harboring replication-competent virus under immune pressure.

References

  1. Cao Y, Qin L, Zhang L, Safrit J, Ho DD. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995;332(4):201-208. doi:10.1056/NEJM199501263320401. https://doi.org/10.1056/NEJM199501263320401
  2. Cao Y, Qin L, Zhang L, Safrit J, Ho DD. Virologic and Immunologic Characterization of Long-Term Survivors of Human Immunodeficiency Virus Type 1 Infection. In: Global Challenge of AIDS (S. Karger AG), pp. 65-76. doi:10.1159/000424936. https://doi.org/10.1159/000424936
  3. Cao Y, Qin L, Zhang L, Safrit J, Ho DD. Characterization of long-term survivors of human immunodeficiency virus type 1 infection. Immunol Lett 1996;51(1-2):7-13 (retracted by: Article retraction. Immunol Lett 1998;64(1):following 55). doi:10.1016/0165-2478(96)02548-5. https://doi.org/10.1016/0165-2478(96)02548-5
  4. Walker CM, Moody DJ, Stites DP, Levy JA. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 1986;234(4783):1563-1566. doi:10.1126/science.2431484. https://doi.org/10.1126/science.2431484
  5. Huang Y, Zhang L, Ho DD. Characterization of nef sequences in long-term survivors of human immunodeficiency virus type 1 infection. J Virol 1995;69(1):93-100. doi:10.1128/JVI.69.1.93-100.1995. https://doi.org/10.1128/JVI.69.1.93-100.1995
  6. Zhang L, Huang Y, Yuan H, Chen BK, Ip J, Ho DD. Genotypic and phenotypic characterization of long terminal repeat sequences from long-term survivors of human immunodeficiency virus type 1 infection. J Virol 1997;71(7):5608-5613. doi:10.1128/JVI.71.7.5608-5613.1997. https://doi.org/10.1128/JVI.71.7.5608-5613.1997
  7. Huang Y, Zhang L, Ho DD. Characterization of gag and pol sequences from long-term survivors of human immunodeficiency virus type 1 infection. Virology 1998;240(1):36-49. doi:10.1006/viro.1997.8913. https://doi.org/10.1006/viro.1997.8913
  8. Binley JM, Jin X, Huang Y, Zhang L, Cao Y, Ho DD, Moore JP. Persistent antibody responses but declining cytotoxic T-lymphocyte responses to multiple human immunodeficiency virus type 1 antigens in a long-term nonprogressing individual with a defective p17 proviral sequence and no detectable viral RNA expression. J Virol 1998;72(4):3472-3474. doi:10.1128/JVI.72.4.3472-3474.1998. https://doi.org/10.1128/JVI.72.4.3472-3474.1998
  9. Deacon NJ, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker DJ, McPhee DA, Greenway AL, Ellett A, Chatfield C, Lawson VA, Crowe S, Maerz A, Sonza S, Learmont J, Sullivan JS, Cunningham A, Dwyer D, Dowton D, Mills J. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 1995;270(5238):988-991. doi:10.1126/science.270.5238.988. https://doi.org/10.1126/science.270.5238.988
  10. Learmont JC, Geczy AF, Mills J, Ashton LJ, Raynes-Greenow CH, Garsia RJ, Dyer WB, McIntyre L, Oelrichs RB, Rhodes DI, Deacon NJ, Sullivan JS. Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort. N Engl J Med 1999;340(22):1715-1722. doi:10.1056/NEJM199906033402203. https://doi.org/10.1056/NEJM199906033402203
  11. Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995;270(5243):1811-1815. doi:10.1126/science.270.5243.1811. https://doi.org/10.1126/science.270.5243.1811
  12. Zhang L, Yu W, He T, Yu J, Caffrey RE, Dalmasso EA, Fu S, Pham T, Mei J, Ho JJ, Zhang W, Lopez P, Ho DD. Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1 activity of CD8 antiviral factor. Science 2002;298(5595):995-1000 (retracted by: Zhang L, Lopez P, He T, Yu W, Ho DD. Retraction of an interpretation. Science 2004;303(5657):467. doi:10.1126/science.303.5657.467b). doi:10.1126/science.1076185. https://doi.org/10.1126/science.1076185
  13. Mackewicz CE, Yuan J, Tran P, Diaz L, Mack E, Selsted ME, Levy JA. alpha-Defensins can have anti-HIV activity but are not CD8 cell anti-HIV factors. AIDS 2003;17(14):F23-F32. doi:10.1097/00002030-200309260-00001. https://doi.org/10.1097/00002030-200309260-00001
  14. Levy JA. The search for the CD8+ cell anti-HIV factor (CAF). Trends Immunol 2003;24(12):628-632. doi:10.1016/j.it.2003.10.005. https://doi.org/10.1016/j.it.2003.10.005
  15. Shridhar V, Chen Y, Gupta P. The CD8 antiviral factor (CAF) can suppress HIV-1 transcription from the long terminal repeat (LTR) promoter in the absence of elements upstream of the CATATAA box. Virol J 2014;11:130. doi:10.1186/1743-422X-11-130. https://doi.org/10.1186/1743-422X-11-130
  16. Morvan MG, Teque FC, Locher CP, Levy JA. The CD8(+) T Cell Noncytotoxic Antiviral Responses. Microbiol Mol Biol Rev 2021;85(2):e00155-20. doi:10.1128/MMBR.00155-20. https://doi.org/10.1128/MMBR.00155-20
  17. Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, Zhang K, Gumbs C, Castagna A, Cossarizza A, Cozzi-Lepri A, De Luca A, Easterbrook P, Francioli P, Mallal S, Martinez-Picado J, Miro JM, Obel N, Smith JP, Wyniger J, Descombes P, Antonarakis SE, Letvin NL, McMichael AJ, Haynes BF, Telenti A, Goldstein DB. A whole-genome association study of major determinants for host control of HIV-1. Science 2007;317(5840):944-947. doi:10.1126/science.1143767. https://doi.org/10.1126/science.1143767
  18. International HIV Controllers Study; Pereyra F, Jia X, McLaren PJ, Telenti A, de Bakker PIW, Walker BD, Ripke S, Brumme CJ, Pulit SL, Carrington M, Kadie CM, Carlson JM, Heckerman D, Graham RR, Plenge RM, Deeks SG, Gianniny L, Crawford G, Sullivan J, Gonzalez E, Davies L, Camargo A, Moore JM, Beattie N, Gupta S, Crenshaw A, Burtt NP, Guiducci C, Gupta N, Gao X, Qi Y, Yuki Y, Piechocka-Trocha A, Cutrell E, Rosenberg R, Moss KL, Lemay P, O'Leary J, Schaefer T, Verma P, Toth I, Block B, Baker B, Rothchild A, Lian J, Proudfoot J, Alvino DM, Vine S, Addo MM, Allen TM, Altfeld M, Henn MR, Le Gall S, Streeck H, Haas DW, Kuritzkes DR, Robbins GK, Shafer RW, Gulick RM, Shikuma CM, Haubrich R, Riddler S, Sax PE, Daar ES, Ribaudo HJ, Agan B, Agarwal S, et al. (consortium publication). The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 2010;330(6010):1551-1557. doi:10.1126/science.1195271. https://doi.org/10.1126/science.1195271
  19. Deeks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 2007;27(3):406-416. doi:10.1016/j.immuni.2007.08.010. https://doi.org/10.1016/j.immuni.2007.08.010
  20. Jiang C, Lian X, Gao C, Sun X, Einkauf KB, Chevalier JM, Chen SMY, Hua S, Rhee B, Chang K, Blackmer JE, Osborn M, Peluso MJ, Hoh R, Somsouk M, Milush J, Bertagnolli LN, Sweet SE, Varriale JA, Burbelo PD, Chun TW, Laird GM, Serrao E, Engelman AN, Carrington M, Siliciano RF, Siliciano JM, Deeks SG, Walker BD, Lichterfeld M, Yu XG. Distinct viral reservoirs in individuals with spontaneous control of HIV-1. Nature 2020;585(7824):261-267. doi:10.1038/s41586-020-2651-8. https://doi.org/10.1038/s41586-020-2651-8
  21. Lian X, Gao C, Sun X, Jiang C, Einkauf KB, Seiger KW, Chevalier JM, Yuki Y, Martin M, Hoh R, Peluso MJ, Carrington M, Ruiz-Mateos E, Deeks SG, Rosenberg ES, Walker BD, Lichterfeld M, Yu XG. Signatures of immune selection in intact and defective proviruses distinguish HIV-1 elite controllers. Sci Transl Med 2021;13(624):eabl4097. doi:10.1126/scitranslmed.abl4097. https://doi.org/10.1126/scitranslmed.abl4097
  22. Veenhuis RT, Kwaa AK, Garliss CC, Latanich R, Salgado M, Pohlmeyer CW, Nobles CL, Gregg J, Scully EP, Bailey JR, Bushman FD, Blankson JN. Long-term remission despite clonal expansion of replication-competent HIV-1 isolates. JCI Insight 2018;3(18):e122795. doi:10.1172/jci.insight.122795. https://doi.org/10.1172/jci.insight.122795
  23. Gasca-Capote C, Lian X, Gao C, Roseto IC, Jiménez-León MR, Gladkov G, Camacho-Sojo MI, Pérez-Gómez A, Gallego I, Lopez-Cortes LE, Bachiller S, Vitalle J, Rafii-El-Idrissi Benhnia M, Ostos FJ, Collado-Romacho AR, Santos J, Palacios R, Gomez-Ayerbe C, Muñoz-Medina L, Ruiz-Sancho A, Frias M, Rivero-Juarez A, Roca-Oporto C, Hidalgo-Tenorio C, Rull A, Olalla J, Lopez-Ruz MA, Vidal F, Viladés C, Mastrangelo A, Cavassini M, Espinosa N, Perreau M, Peraire J, Rivero A, Lopez-Cortes LF, Lichterfeld M, Yu XG, Ruiz-Mateos E. The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers. J Clin Invest 2024;134(8):e174215. doi:10.1172/JCI174215. https://doi.org/10.1172/JCI174215
  24. Mastrangelo A, Banga R, Perreau M. Elite and posttreatment controllers, two facets of HIV control. Curr Opin HIV AIDS 2022;17(5):325-332. doi:10.1097/COH.0000000000000751. https://doi.org/10.1097/COH.0000000000000751
  25. Turk G, Seiger K, Lian X, Sun W, Parsons EM, Gao C, Rassadkina Y, Polo ML, Czernikier A, Ghiglione Y, Vellicce A, Varriale J, Lai J, Yuki Y, Martin M, Rhodes A, Lewin SR, Walker BD, Carrington M, Siliciano R, Siliciano J, Lichterfeld M, Laufer N, Yu XG. A Possible Sterilizing Cure of HIV-1 Infection Without Stem Cell Transplantation. Ann Intern Med 2022;175(1):95-100. doi:10.7326/L21-0297. https://doi.org/10.7326/L21-0297
  26. Benito JM, Lopez-Bernaldo JC, Fisher K, Pereyra-Casanova A, Cabello A, Estrada V, Gorgolas M, Buzon MJ, Palmer S, Rallon N. Functional cure of HIV-1 infection in an exceptional elite controller: a case report. Lancet HIV 2025;12(12):e850-e860. doi:10.1016/S2352-3018(25)00233-4. https://doi.org/10.1016/S2352-3018(25)00233-4
  27. Noel N, Lambotte O. The elite controller phenotype. Curr Opin HIV AIDS 2026;21(3):212-217. doi:10.1097/COH.0000000000001027. https://doi.org/10.1097/COH.0000000000001027