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Review
. 2020 Jan 31:11:46.
doi: 10.3389/fmicb.2020.00046. eCollection 2020.

Lessons Learned From Failures and Success Stories of HIV Breakthroughs: Are We Getting Closer to an HIV Cure?

V Kalidasan  1 , Kumitaa Theva Das  1
Affiliations
Review

Lessons Learned From Failures and Success Stories of HIV Breakthroughs: Are We Getting Closer to an HIV Cure?

V Kalidasan et al. Front Microbiol. .

Abstract

There is a continuous search for an HIV cure as the success of ART in blocking HIV replication and the role of CD4+ T cells in HIV pathogenesis and immunity do not entirely eradicate HIV. The Berlin patient, who is virus-free, serves as the best model for a 'sterilizing cure' and many experts are trying to mimic this approach in other patients. Although failures were reported among Boston and Essen patients, the setbacks have provided valuable lessons to strengthen cure strategies. Following the Berlin patient, two more patients known as London and Düsseldorf patients might be the second and third person to be cured of HIV. In all the cases, the patients underwent chemotherapy regimen due to malignancy and hematopoietic stem cell transplantation (HSCT) which required matching donors for CCR5Δ32 mutation - an approach that may not always be feasible. The emergence of newer technologies, such as long-acting slow-effective release ART (LASER ART) and CRISPR/Cas9 could potentially overcome the barriers due to HIV latency and persistency and eliminate the need for CCR5Δ32 mutation donor. Appreciating the failure and success stories learned from these HIV breakthroughs would provide some insight for future HIV eradication and cure strategies.

Keywords: Berlin patient; Boston patients; Düsseldorf patient; Essen patient; HIV eradication and cure; London patient; Mississippi baby; elite controllers.

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Figures

FIGURE 1
FIGURE 1
Timeline covers the highlights over the past three decades of HIV/AIDS. The history of HIV/AIDS epidemic begins from the first reported cases in 1981 of an unknown virus. The scientific and medical advances, such as the development of antiretroviral therapy (ART), cure breakthrough in Berlin patient, and other emerging initiatives for HIV eradication and cure strategies.
FIGURE 2
FIGURE 2
Combination of the CRISPR/Cas9 system and LASER ART as HIV eradication and cure strategies. (A) CRISPR/Cas9 can potentially be utilized for knockout, activation or base-editing depending on the nature of the therapy. CRISPR/Cas9 consists of a sgRNA and Cas9. CRISPR/Cas9 is typically delivered as a transgene in a transfer vector. The transfer plasmid, packaging plasmid and helper plasmid (envelope) is packaged to form a viral vector. The vector can be either delivered (ii) directly, by injecting in vivo into the infected patient, or (ii) cell-based, by first harvesting the hematopoietic stem cell (HSC) from the infected patient, and followed by transfecting the cells with viral vector containing the Cas9-sgRNA. After the ex vivo HSC modification, the clone containing the edited cells will be reinfused back into the HIV positive patient. (B) Based on LATTE-2 trial, currently two LASER ART are available (LA-RPV and LA-CAB). The production of LA-ARV involves conversion of native drug into hydrophobic lipophilic component. Cytotoxicity, pharmacokinetic and pharmacodynamic is performed to test the drug safety and efficacy. The drugs can be administrated by mean of antibody, intravaginal ring, implant or injection delivery. Upon reaching the target anatomical site, the nanocrystal will be broken down to release the active drug and further therapeutic action taken place.
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