IAS–USA Topics in Antiviral Medicine Perspective What Will It Take to Cure HIV? Investigational strategies to attempt HIV cure or remission include very detectable virus during 3 years of treat- early initiation of antiretroviral therapy to limit the latent HIV reservoir and ment but exhibited viral rebound 2 preinfection vaccination. In the setting of viral suppression, strategies include weeks to 3 weeks after stopping treat- reactivation of latently infected cells (eg, through “shock” therapy with ment. Similarly, an HIV-infected baby histone deacetylase inhibitors or other agents); use of broadly neutralizing in Milan began antiretroviral treatment antibodies, therapeutic vaccines, immunotoxins, or other immune-based 12 hours after birth and had no detect- therapies to kill latently infected cells; and gene editing to induce target able virus for 3 years while receiving cell resistance (eg, by eliminating the CC chemokine receptor 5 [CCR5] treatment but exhibited viral rebound 2 coreceptor). Improved ability to detect and quantify very low levels of virus weeks to 3 weeks after stopping treat- is needed. This article summarizes a presentation by Jintanat Ananworanich, ment.5-9 MD, PhD, at the IAS–USA continuing education program held in New York, In general, it is believed that earlier New York, in October 2014. initiation of antiretroviral therapy and the longer it is maintained improve the Keywords: HIV, cure, remission, viral reservoir, latent infection chance of limiting the viral reservoir and achieving HIV remission. How- ever, among the infants who eventually HIV cure research currently focuses 7 months, respectively, after receiv- exhibited rebound after stopping anti- on 2 goals: complete eradication of ing bone marrow transplantation with retroviral therapy, time to viral rebound HIV from the body and HIV remission. cells that included the CCR5 corecep- was longest for the Mississippi baby During remission, virus can still be de- tor. The HIV-infected Mississippi baby, despite a later start of therapy (30 tected at low levels in cells or through born to an HIV-infected mother who hours) than the Canadian baby (<24 ultrasensitive testing in plasma, but did not receive antiretroviral therapy, hours) or the Milan baby (12 hours) antiretroviral therapy is not necessary began antiretroviral therapy at 30 hours and a shorter duration of therapy (18 unless continued monitoring reveals after birth. HIV infection was confirmed months, 3 years, and 3 years, respec- increased viremia. and the infant achieved viral suppres- tively). The baseline HIV RNA level of sion 1 month after starting treatment. the Mississippi baby (19,812 copies/ Cases of Remission and Effects Treatment was stopped after 18 months mL) was between that of the Canadian of Antiretroviral Therapy in because the child was lost to follow- baby (808 copies/mL) and the Milan Infants With Early Acute HIV up care, and no virus was detected baby (152,560 copies/mL). The Missis- Infection for a subsequent 27 months. In mid- sippi baby’s longer remission period 2014, the child’s plasma HIV RNA level might be partially explained by the Timothy R. Brown, also referred to as rebounded to 10,000 copies/mL to shorter duration of antiretroviral ther- the Berlin patient, remains the only 16,000 copies/mL, and it was subse- apy before an HIV RNA level of less known person in whom HIV appears quently determined that HIV RNA level than 50 copies/mL was achieved (1 to be eradicated. Brown stopped taking had increased to 9 copies/mL 2 weeks month of therapy for the Mississippi 1-4 antiretroviral therapy approximately 7 before the rebound. baby vs 6 months for the Canadian years ago and has had no detectable There have been several other cases baby and 3 months for the Milan baby). virus capable of replicating since. The of infants who received antiretroviral Testing performed while the Missis- mechanism of the possible eradica- therapy during early acute HIV infec- sippi baby was in remission and was tion in this case included bone marrow tion, resulting in the absence of de- not taking antiretroviral therapy and the transplantation with cells lacking the tectable virus. An HIV-infected baby in Milan baby and Canadian baby were CC chemokine receptor 5 (CCR5) core- California who received antiretroviral taking antiretroviral therapy showed ceptor, rendering the cells resistant treatment at 4 hours after birth contin- that whereas all 3 had negative test to HIV infection. Two other patients, ued therapy for 14 months with no de- results for HIV DNA in peripheral blood, referred to as the Boston patients, ex- tectable cellular or plasma virus. Four replication-competent virus, and anti- perienced HIV remission 3 months and HIV-infected Canadian babies who re- HIV antibody, the Canadian baby and ceived antiretroviral treatment within the Milan baby displayed evidence sug- their first 24 hours have remained on gestive of ongoing viral replication. The Dr Ananworanich is Associate Director for HIV Therapeutics Research at the US Military treatment for 2.5 years to 7 years with Milan baby had detectable HIV-specific HIV Research Program and the Henry M. no detectable virus. Another Canadian T cells and a high percentage of acti- Jackson Foundation for the Advancement baby who received antiretroviral treat- vated T cells, and the Canadian baby of Military Medicine in Bethesda, Maryland. ment within 24 hours of birth had no had detectable cell-associated HIV RNA 80 HIV Cure Volume 23 Issue 2 May/June 2015 6 (A) Blood DNA 6 (B) Lymph node DNA central memory cells are longer lived 5 5 and constitute a latently infected cel- cells cells 6 6 lular reservoir during HIV infection. 4 4 During chronic HIV infection, the la- 3 3 tent reservoir is large and central 2 2 memory CD4+ cell infections still con- DNA copies/10 DNA copies/10 stitute a major part of the latently 1 1 10 10 infected cell pool even after years of Log Log 0 0 0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 100 120 140 160 180 antiretroviral therapy. The reservoir size is much smaller during acute HIV 6 (C) Gut DNA 8 (D) Blood RNA infection, with years of antiretroviral 7 5 cells therapy resulting in a marked decrease 6 6 4 in latently infected cells. 5 Levels of integrated HIV DNA were 3 4 ART interruption examined among HIV-infected patients 3 2 in Thailand who started antiretroviral 2 DNA copies/10 10 1 therapy within 2 weeks of infection, 1 Log 0 0 within 3 weeks to 4 weeks of infec- 0 20 40 60 80 100 120 140 160 180 HIV RNA in Blood (copies/mL) 0 50 100 150 200 250 300 tion, or during chronic infection, and Time After SIV Infection (Days) had plasma viral loads below detection limits at 2 years.12 Starting treatment Figure 1. Simian immunodeficiency virus (SIV) proviral DNA was detected in the lymph nodes within the first 2 weeks of infection (B) and gut (C) but not in peripheral blood (A) after antiretroviral therapy (ART) was initiated in resulted in much lower levels of inte- macaques 3 days after infection. All macaques had detectable blood HIV RNA after interrup- grated HIV DNA in all CD4+ cell sub- 11 tion of ART (D). Adapted from Whitney et al. sets than when antiretroviral therapy was initiated during chronic HIV infec- levels; these findings were not present Is Early Antiretroviral Therapy tion, and persistence of the viral res- in the Mississippi baby.2,5,8 Crucial to Limiting HIV ervoir was intermediate among pa- These cases of transient HIV remis- Persistence? tients starting antiretroviral therapy at sion also show how current tools are 3 weeks to 4 weeks after infection. limited in their ability to detect low Initiation of antiretroviral therapy in Studies in the VISCONTI (Virological numbers of HIV-infected cells. Acute macaques 3 days after establishment and Immunological Studies in Con- HIV infection is associated with low of simian immunodeficiency virus (SIV) trollers After Treatment Interruption) levels of HIV DNA, which are further infection resulted in undetectable pro- cohort of posttreatment controllers— reduced by antiretroviral therapy dur- viral DNA levels in peripheral blood a group of 14 patients in France who ing early acute infection to levels that but not in the lymph nodes or gut, started antiretroviral therapy early may be undetectable. Currently, whether with DNA levels at these sites declining and exhibited control of viremia after virus is present or in what amount it during 6 months of treatment (Figure interrupting treatment for 6 years or is present cannot be determined below 1).11 Viral rebound was observed when more—showed that early treatment the detection limits of current assays. antiretroviral treatment was stopped, could skew the distribution of latently Potential methods for measuring on- suggesting that seeding of the viral HIV-infected cells to shorter-lived tran- going viral replication in the reser- reservoir begins very early and that sitional memory cells that may be voir include measurement of cell- initiation of treatment at 3 days in this more rapidly cleared by the immune associated HIV RNA, single-copy HIV animal model is not early enough to system (Figure 2).13 RNA, and replication-competent vi- prevent it. rus using viral outgrowth assays. Re- The size and composition of the la- Strategies to Eliminate HIV cently, it has been shown that the tent HIV reservoir are affected by early Persistence replication-competent HIV reservoir antiretroviral therapy. In basic CD4+ may be 60 times greater than what cell differentiation, stimulation of naive One HIV remission and cure strategy is currently measured by viral out- CD4+ cells by antigens causes them to currently under investigation is pre- growth assay, as there are viruses differentiate into memory CD4+ cells infection vaccination.