The Challenge of Finding a Cure for HIV Infection

Although combination therapy for HIV infection represents a triumph for modern medicine, chronic suppressive therapy is required to contain persistent infection in reservoirs such as latently infected CD4+ lymphocytes and cells of the macrophage-monocyte lineage. Despite its success, chronic suppressive therapy is limited by its cost, the requirement of lifelong adherence, and the unknown effects of long-term treatment. This review discusses our current understanding of suppressive antiretroviral therapy, the latent viral reservoir, and the needs for and challenges of attacking this reservoir to achieve a cure. Human immunodeficiency virus 1 (HIV-1), identified 28 years ago,1 remains a global health threat responsible for a worldwide pandemic with an estimated 33 million people infected.2 More than 7000 new HIV infections occur each day, and the number of newly diagnosed infections remains far greater than the number of people (around 50%) who have access to highly active antiretroviral therapy (HAART). Advances have been made in treating AIDS since the introduction of HAART in 1996. This has transformed a lethal disease into a chronic pathology, with a dramatic decrease of mortality and morbidity of AIDS-related symptoms in infected patients.3,4 To date, the only way to treat patients infected with HIV relies on a combination of drugs that acts at different stages of the viral life cycle, preventing the virus from replicating. These molecules target four stages of the cycle: viral entry, reverse transcription of the viral genome, integration into the genome of the host cell and maturation of viral proteins. This therapy can reduce plasma virus levels below detection limits (≤50 copies/mL). However, with very sensitive but expensive and technically challenging methods, a residual viraemia is still detected in patients on HAART.5–8 Moreover, HIV RNA typically returns to a measurable plasma level in less than 2 weeks when HAART is interrupted, suggesting that even long-term suppression of HIV-1 replication by HAART fails to totally eliminate HIV-1. These two latter phenomena are mainly due to the existence of HIV reservoirs.6,9–13 The existence of integrated latent viruses or virus replicating at a very low level in different cellular reservoirs is an obstacle to the eradication of the virus, and thus the total recovery of patients, and requires strict adherence to lifelong treatment.14–21 In addition, these cellular reservoirs are often found in tissue sanctuaries, such as the brain, where drug penetration may be several orders of magnitude lower than in other tissues.16,18 Viral clearance from other reservoirs, such as from chronically infected macrophages, is also difficult since reverse transcriptase inhibitors are usually ineffective and protease inhibitors have significantly lower activities in these cells than in lymphocytes.22,23 Moreover, emergence of many side effects may require the cessation of treatment.24 Furthermore, the development of many types of resistance, related to the extreme mutability of the virus and in part to treatment interruptions, has been described in the literature.25–28 Another major concern is related to non-AIDS events and non-AIDS mortality in patients having a residual viraemia and a normal CD4+ count, a situation also described in some HIV non-progressors. Owing to the residual viraemia, patients develop chronic inflammation that leads to several complications, for instance, cardiovascular disease, nephropathy, faster evolution of viral hepatitis and cancer.29–33 Last but not least, a major problem related to HAART is the cost of the treatment. Even the cost associated with the cheaper generic forms of the drugs far exceeds the abilities of many resource-limited countries in providing treatment. The cost of this treatment will be increasingly important in the future, with an overall global budget requirement to address this problem from today to 2031 being estimated at US$397–727 billion.34 Since, to date, no effective HIV-1 vaccine is available,35–38 it appears crucial to improve HAART and to develop new strategies to cure HIV.39,40