Worldwide, approximately 37.7 million individuals live with HIV, with approximately 1.1 million such individuals in the United States alone.1,2
Despite the widespread implementation of highly effective antiretroviral therapy (ART) and subsequent validation of the “undetectable equals untransmittable,” or U=U, concept, 1.7 million new cases occur annually alongside nearly 770,000 AIDS-related deaths.1,3
Although the cure for HIV has been a priority since the virus’ discovery, it remains elusive.
THE TYPES OF “CURE”
The FDA defines HIV cure research as “any investigation that evaluates (1) a therapeutic intervention or approach that controls or eliminates HIV infection to the point where no further medical interventions are needed to maintain health, and (2) preliminary scientific concepts that might ultimately lead to such a therapeutic intervention.”4
Thus, the medical community is pursuing 2 types of HIV cure: eradicative and functional, also called HIV remission. Eradication, also known as sterilization, implies that HIV has been removed completely from the human host.5
A functional cure differs significantly because the goal is not to clear the viral reservoir from the human host but rather to reach sustainable infection control in the absence of ART.6
CHALLENGES IN CREATING A CURE FOR HIV-1
ART targets only viral replication in activated cells. It cannot touch latent virus, meaning the vast amount of virus hidden in memory or otherwise inactive T cells. This reservoir poses the biggest challenge to HIV elimination, as viral latency is a reversible process in the absence of effective ART.7
While patients are on ART, this latent pool of cells declines slowly but may take an estimated 7 decades to fall to 0; recent research has also described a decline of only 4 years followed by a plateau. A unique hypothesis of this persistence centers on the ability of the infected cells to expand via clonal proliferation rather than active HIV replication to sustain the viral reservoir.7-10
Complicating viral latency further, a latent reservoir may form in compartments of the human body that are spared from immune recognition and ART because of both physical and cellular barriers (also called viral escape). Some examples of these barriers include the blood-brain barrier, the Sertoli cell layer of the testes, and the B-cell follicles within the lymph nodes.11
Despite these challenges, 2, and possibly 3, eradicative cures exist. In addition to the CD4 receptor, HIV requires a second coreceptor to infect a cell. One such receptor, the CCR5, is congenitally absent in 0% to 2.3% of individuals.12
The “Berlin Patient” (Timothy Ray Brown), as part of treatment for acute myeloid leukemia (AML), received full-intensity conditioning chemotherapy, whole body radiation, and 2 transplants from an HLA antigen– matched donor with CCR5 coreceptor Δ32 deletion. The “London Patient” (Adam Castillejo), as part of treatment for Hodgkin lymphoma, also received a stem cell transplant from a donor with the CCR5Δ coreceptor Δ32 deletion. However, he did not receive radiation but instead received reduced
intensity conditioning chemotherapy.13,14
Both Brown and Castillejo have been deemed cured (no HIV viremia off ART). A third patient, known as the Düsseldorf patient, remains under evaluation; the 49-year-old man received a bone marrow transplant from a CCR5 coreceptor Δ32 deletion donor in February 2013 for AML. Physicians discontinued ART in November 2018, and the patient’s HIV remained undetectable as of March 2020.15
No single approach has achieved long-term viral remission. Described here are several approaches that investigators are evaluating for a functional cure that may be used in combination: early initiation, shock and kill (including several potential components), clustered regularly interspaced short palindromic repeats (CRISPR), and chimeric antigen receptor (CAR) T-cell technology.
Early initiation of ART upon diagnosis of HIV has been correlated with varying degrees of posttreatment control, reducing residual viral replication, decreasing viral reservoir, preserving innate immunity, and enhancing immune response.16,17
Several cohorts evaluating treatment interruption (CHAMP/SPARTAC/VISCONTI) concluded that initiation of ART during the early acute phase of HIV infection can preserve CD4+ cell counts and delay viral rebound after ART interruption.17-19
Nevertheless, treatment interruption studies have fallen out of favor given multiple increased risks with ART interruption, as seen in the SMART trial (NCT00027352) (eg, clinical progression, cardiovascular risk, or malignancies).20
New consensus recommendations for analytical ART interruptions in HIV research trials now exist to guide future study designs.21
The shock-and-kill method combines (1) latency reversal agents such as histone deacetylase inhibitors and toll-like receptor (TLR) agonists to induce HIV-1 transcription followed by (2) ART, therapeutic vaccines, and/or broadly neutralizing antibodies (bNAbs) to decrease the latent reservoir. Major histone deacetylase inhibitors romidepsin and vorinostat induce HIV gene transcription by suppressing histone deacetylases enzymes that enzymatically remove the acetyl group from histones.22,23 TLR agonists such as vesatolimod induce the secretion of tumor necrosis factor α _and thus promote viral reactivation.24 This process of reactivation is then followed by immunomodulation with agents such as therapeutic vaccines and/or bNAbs. The aim of therapeutic vaccines (such as the modified vaccinia Ankara B and the recombinant canarypox virus) is to elicit an antigenic immune response to suppress viral replication in the absence of ART. Broadly neutralizing antibodies (such as VRC01 and 3BNC117) induce host immunity by targeting specific epitopes of HIV.22,25
Combined approaches using these methods were presented at the 2020 virtual Conference on Retroviruses and Opportunistic Infections. Notable studies included (1) a 20-patient cohort given romidepsin and bNAb 3BNC117, resulting in neither delay of viral rebound nor reduction in reservoir size, and (2) the safety and efficacy of a combination TLR7 agonist/therapeutic vaccine approach to induce CD8+ T cell–mediated control of the simian immunodeficiency virus (a commonly used nonhuman primate model), finding no statistically significant differences between treatment and placebo. The authors did report a modest increase in time to viral rebound with this strategy.26,27
Of note, these novel drug mechanisms are only limited examples of the vast array of immunoregulatory agents under development. Agents such as immune checkpoint inhibitors, PD-1 and CTLA-4 agents, may possibly be used in combination to enhance the response of HIV-specific T cells and improve viral control.28,29
Emerging strategies and evolving science regarding genetic modification have unlocked new approaches for HIV cure research. These approaches include using CRISPR and CAR T-cell technology. CRISPR enables DNA cleavage to occur prior to proviral integration (resulting in proviral destruction) or after proviral integration (resulting in small insertions and deletions in the HIV genome).30-33
CAR T-cell technology uses cytotoxic T cells engineered with extracellular components to recognize both HIV epitopes and intracellular components with accompanying signal inductions.34
Although current research has not yet elucidated the path to either “cure” approach, research remains highly prioritized and active, with promising novel drug mechanisms and emerging science. Evolving methods have redefined the concept of HIV cure, with the eventual goal of bringing the story of HIV to its completion.
Xu is a postgraduate year 1 pharmacy practice resident at the Jeanes Campus of the Temple University Health System in Philadelphia, Pennsylvania.
Koren is an infectious diseases clinical pharmacist at the Temple University Health System and an adjunct assistant clinical professor at the Lewis Katz School of Medicine at Temple University. *He is an active member of the Society of Infectious Diseases Pharmacists.
- Data and statistics. World Health Organization. https://www.who.int/hiv/data/en/. Published July 30, 2019. Accessed April 13, 2020.
- Centers for Disease Control. U.S. Statistics. HIV.gov. https://www.hiv.gov/hiv-basics/overview/data-and-trends/statistics. Published January 16, 2020. Accessed April 13, 2020.
- Eisinger RW, Dieffenbach CW, Fauci AS. HIV Viral Load and Transmissibility of HIV Infection: Undetectable Equals Untransmittable. JAMA. 2019;321(5):451-2.
- FDA (2013) HIV patient-focused drug development backgrounder document. [http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM354549.pdf]
- Dubé K, Luter S, Lesnar B, et al. Use of 'eradication' in HIV cure-related research: a public health debate. BMC Public Health. 2018;18(1):245.
- Davenport MP, Khoury DS, Cromer D, Lewin SR, Kelleher AD, Kent SJ. Functional cure of HIV: the scale of the challenge. Nat Rev Immunol. 2019;19(1):45-54.
- Pitman MC, Lewin SR. Towards a cure for human immunodeficiency virus. Intern Med J. 2018;48(1):12-5.
- Besson GJ, Lalama CM, Bosch RJ, et al. HIV-1 DNA decay dynamics in blood during more than a decade of suppressive antiretroviral therapy. Clin Infect Dis. 2014;59(9):1312-21.
- Siliciano RF, Greene WC. HIV latency. Cold Spring Harb Perspect Med. 2011;1(1):a007096.
- Reeves DB, Duke ER, Wagner TA, Palmer SE, Spivak AM, Schiffer JT. A majority of HIV persistence during antiretroviral therapy is due to infected cell proliferation. Nat Commun. 2018;9(1):4811.
- Stein J, Storcksdieck Genannt Bonsmann M, Streeck H. Barriers to HIV Cure. HLA. 2016;88(4):155-63.
- Solloch UV, Lang K, Lange V, Böhme I, Schmidt AH, Sauter J. Frequencies of gene variant CCR5-Δ32 in 87 countries based on next-generation sequencing of 1.3 million individuals sampled from 3 national DKMS donor centers. Hum Immunol. 2017;78(11-12):710-7.
- Brown TR, Brown TR. I am the Berlin patient: a personal reflection. AIDS Res Hum Retroviruses. 2015;31(1):2-3.
- Gupta RK, Peppa D, Pace M, Thornhill JP, Nastouli E, Grant P, McCoy L, Innes A, Simon Edwards S, Annemarie. Sustained hiv remission in the london patient: the case for hiv cure. Presented at: 27th Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Boston, Massachusetts.
- Jensen BO, Knops E, Lübke N , Wensing A, Martinez-Picado J, Kaiser R, Nijhuis M, Salgado M, Harrer T, Heger E, Eberhard JM, Hauber I, Münk C, Häussinger D, Kobbe G. Analytic treatment interruption (ati) after allogeneic ccr5-d32 hsct for aml in 2013. Presented at: 27th Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Boston, Massachusetts.
- Etemad B, Esmaeilzadeh E, Li JZ. Learning From the Exceptions: HIV Remission in Post-treatment Controllers.Front Immunol. 2019;10:1749.
- Sáez-Cirión A, Bacchus C, Hocqueloux L, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9(3):e1003211.
- Namazi G, Fajnzylber JM, Aga E, et al. The Control of HIV After Antiretroviral Medication Pause (CHAMP) Study: Posttreatment Controllers Identified From 14 Clinical Studies. J Infect Dis. 2018;218(12):1954-63.
- Fidler S, Porter K, Ewings F, et al. Short-course antiretroviral therapy in primary HIV infection. N Engl J Med. 2013;368(3):207-17.
- Li JZ, Smith DM, Mellors JW. The need for treatment interruption studies and biomarker identification in the search for an HIV cure. AIDS. 2015;29(12):1429-32.
- Julg B, Dee L, Ananworanich J, et al. Recommendations for analytical antiretroviral treatment interruptions in HIV research trials-report of a consensus meeting. Lancet HIV. 2019;6(4):e259-e268.
- Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014;6:43.
- Macedo AB, Novis CL, De Assis CM, et al. Dual TLR2 and TLR7 agonists as HIV latency-reversing agents. JCI Insight. 2018;3(19):122673.
- Grau-Expósito J, Luque-Ballesteros L, Navarro J, et al. Latency reversal agents affect differently the latent reservoir present in distinct CD4+ T subpopulations. PLoS Pathog. 2019;15(8):e1007991.
- Landais E, Moore PL. Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers. Retrovirology. 2018;15(1):61.
- Gruell H, Cohen YZ, Gunst JD, Pahus MH, Lehmann C, Millard K, Tolstrup M, Lorenzi JC, Nussenzweig M. A randomized trial of the impact of 3bnc117 and romidepsin on the hiv-1 reservoir. Presented at: 27th Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Boston, Massachusetts.
- SenGupta D, Ramgopal M, Brinson C, DeJesus E, Mills A, Shalit P, McCallister S, Graham H, Patet H, Zhong L. Safety and analytic treatment interruption outcomes of vesatolimod in hiv controllers. Presented at: 27th Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Boston, Massachusetts.
- Kaufmann DE, Walker BD. PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J Immunol. 2009;182(10):5891-7.
- Harper, J., Gordon, S., Chan, C.N. et al. CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption. Nat Med (2020).
- Ebina H, Misawa N, Kanemura Y, Koyanagi Y. Harnessing the CRISPR/Cas9 system to disrupt latent HIV-1 provirus. Sci Rep. 2013;3:2510.
- Zhu W, Lei R, Le Duff Y, et al. The CRISPR/Cas9 system inactivates latent HIV-1 proviral DNA. Retrovirology. 2015;12:22.
- Mefferd AL, Bogerd HP, Irwan ID, Cullen BR. Insights into the mechanisms underlying the inactivation of HIV-1 proviruses by CRISPR/Cas. Virology. 2018;520:116-26.
- Dash PK, Kaminski R, Bella R, et al. Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice. Nat Commun. 2019;10(1):2753.
- Kuhlmann AS, Peterson CW, Kiem HP. Chimeric antigen receptor T-cell approaches to HIV cure. Curr Opin HIV AIDS. 2018;13(5):446-53.