Editorial: Forty Years of Waiting for Prevention and Cure of HIV Infection – Ongoing Challenges and Hopes for Vaccine Development and Overcoming Antiretroviral Drug Resistance

In May 1983, a new human retrovirus was identified and isolated in the laboratory of Louis Montagnier and colleagues at the Pasteur Institute in Paris [1]. In April 1984, 40 years ago, the Secretary of the US Department of Health and Human Services announced that Dr. Robert Gallo and his colleagues at the National Cancer Institute (NCI) had confirmed the cause of acquired immunodeficiency syndrome (AIDS) as a retrovirus, which they initially named, human T-lymphotropic virus type III (HTLV-III) [2,3]. The virus was renamed human immunodeficiency virus (HIV) in 1986 [4]. There were initial hopes for a cure for HIV infection and for vaccine prevention. However, 40 years on, at the beginning of 2024, the World Health Organization (WHO) now estimates that since the HIV epidemic began more than 40 years ago, between 65.0 million and 113.0 million people have been infected with HIV [5]. Between 32.9 million and 51.3 million people have died due to the effects of HIV infection [5]. At the end of 2022, between 33.1 million and 45.7 million people were living with HIV, which means that between 0.6% and 0.8% of adults aged 15–49 years worldwide were living with HIV [5]. Rates of infection vary between countries, and the WHO African Region is most severely affected, with an estimated 3.2% (1 in every 25) of adults in this region living with HIV, which accounts for more than two-thirds of the global population who live with HIV [5]. Since 1983, when the retrovirus that caused HIV infection and AIDS was first identified, each decade has inspired reviews of developments and disappointment in the prevention, treatment, and management of HIV/AIDS [6,7]. Cure and prevention are the dual ‘holy grail’ sought but still not achieved [6,7]. In the fourth decade since the identification of HIV, there have been some promising developments, some of which are driven by experiences from the recent COVID-19 pandemic [8]. Further challenges include increasing resistance to antiretroviral therapies, which were previously very effective, and increasing antimicrobial resistance to tuberculosis, a potentially fatal infection that is increasingly seen in patients with HIV/AIDS [9,10].

Retroviral vaccine technology to prevent HIV infection has begun to show some promise. History will record that the COVID-19 pandemic, caused by the SARS-CoV-2, resulted in morbidity and mortality worldwide and also had major economic and social consequences, but also drove the development of novel vaccine technology based on mRNA encapsulated in lipid nanoparticles [8,11]. Implementing successful vaccination programs has provided evidence for the advantages of mRNA vaccines, including the low cost of manufacturing, rapid and large-scale vaccine production, and modification of mRNA vaccines in response to emerging SARS-CoV-2 viral variants [11,12]. The mRNA vaccines deliver antigenic proteins directly and rely on the host’s cells to manufacture protein immunogens that induce antibody and cytotoxic T lymphocyte responses [11,12]. Although the history of mRNA-based vaccines goes back almost three decades, it is only recently that the possibility has emerged that mRNA vaccines may be developed to generate neutralizing antibodies and effective T lymphocyte responses to HIV infection, mainly to produce neutralizing antibodies [11,12].

The International AIDS Vaccine Initiative (IAVI) is a global public-private partnership that aims to accelerate vaccine development to prevent HIV infection and AIDS [13,14]. On 2 March 2024, IAVI published a response and update on the status of preliminary mRNA HIV vaccine candidate clinical trials, including GIAVI G002 (NCT05001371), IAVI G003 (NCT05414786), and HVTN 302 (NCT05217641) [14]. This year, continued safety and immunogenicity studies of promising immunogens are planned [14,15]. The Ad26.Mos4.HIV vaccine candidate uses a common-cold virus adenovirus (serotype 26, or Ad26) to deliver mosaic HIV immunogens, with a final two vaccination doses accompanied by a bivalent HIV envelope protein formulation, with combined clade C gp140 and mosaic gp140 envelope proteins [16]. This adjuvanted vaccine includes aluminum phosphate to boost the immune response [16]. The vaccination study program was completed in October 2022 [16]. In January 2023, data from the phase 3 Mosiaco trial, which enrolled 3,900 volunteers in multiple countries, was terminated as the vaccine failed to stop significant infection compared with placebo [17]. However, there are some positive results from several phase 1 studies on generating neutralizing antibodies [18]. Currently, all HIV vaccines in development are in early-stage clinical trials [18]. Despite difficulties in vaccine development, there are some encouraging findings from phase 1 studies on vaccines that generate neutralizing antibodies [18].

Antiretroviral drug resistance has recently become a cause for concern for patients with HIV infection. During the past four decades, methods for the diagnosis of HIV infection and the development and approvals of effective antiretroviral therapies have reduced morbidity and mortality for those infected. There are still no vaccines for disease prevention, and there are still no cures [7]. The lack of transcriptional activity means that latent HIV can escape host immune surveillance, which leads to resistance to antiretroviral therapy (ART) [19,20]. Integrase-strand transfer inhibitors (INSTI) are a vital component of antiretroviral therapy (ART) used for HIV prevention and treatment [19,20]. On 29 February 2024, the WHO published an updated report in response to increasing reports of HIV drug resistance (HIVDR) [21]. Previously, high levels of suppression of HIV viral load (>90%) were reported in HIV-infected patients receiving dolutegravir-containing ART [21]. However, reports of HIVDR to dolutegravir have recently been reported, ranging from 3.9% to 19.6%, in patients with a high HIV viral load [21]. Also, long-acting cabotegravir, which is used for pre-exposure prophylaxis (PrEP) and reduces the risk of acquiring HIV, has shown INSTI resistance [21]. Reports of resistance to HIV antivirals have resulted in updates from the WHO to standardize surveillance of drug resistance in individuals who are HIV-positive and are receiving PrEP [21].

When compared to viral infections that have been eliminated, such as smallpox, HIV has had all the cards stacked against it [7,22]. HIV is a retrovirus infection with modes of transmission that are socially difficult to control, viral diversity, and structural and chemical aspects of the envelope protein that have been challenging for vaccine development [7]. Also, HIV integrates into the host cell, can be dormant with disease latency, and can reactivate [22]. As part of its life cycle, HIV integrates into the host cell DNA, and a subset of the integrated HIV provirus remains transcriptionally silent, or latent, until viral reactivation [22]. The presence of a latent viral reservoir means that curing cases of infection seems unlikely [7].

The HIV Prevention Trials Network (HPTN) is a global collaborative clinical trials network supported by the National Institutes of Health (NIH), which develops and tests the safety and efficacy of interventions to prevent the transmission of HIV [23,24]. The HPTN also aims to organize and promote the prevention, cure, and treatment of HIV/AIDS and diseases impacted by HIV infection [23,24]. Current approaches in the prevention and management of HIV/AIDS aim to prevent or reverse viral latency, develop new vaccines based on new technologies that include mRNA vaccines, modulate T lymphocyte and B lymphocyte immune responses, and improve the prevention and treatment of infections in patients with HIV/AIDS, such as tuberculosis [22,24,25].

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are currently under investigation as antiretroviral agents that can impair the maturation of HIV virions by inhibiting IN interaction with viral genomic RNA [26]. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials (NCT05869643) [26]. Previous cell culture-based viral breakthrough assays identified the HIV-1(Y99H/A128T IN) variant that confers substantial resistance to this inhibitor [26]. By modifying PIR, its analog EKC110 induced hyper-multimerization of INY99H/A128T in vitro and was 14-fold more potent against HIV-1(Y99H/A128T IN) than the parent inhibitor [26]. These findings support a future rationale for developing improved PIR resistance chemotypes and evaluating their potential clinical use [26].

HIV latency is the process by which host cells can harbor full-length HIV proviruses that are replication-competent but transcriptionally inactive [27]. The lack of transcriptional activity means that latent HIV can escape host immune surveillance and makes it insensitive to antiretroviral therapy (ART) [27]. N-803 (nogapendekin alfa inbakicept) consists of two soluble protein subunits of a human interleukin (IL)-15 variant (nogapendekin alfa) bound to the dimeric human IL-15 receptor α (IL-15 Rα) sushi domain/human IgG1 Fc fusion protein (inbakicept) [28]. This novel fusion protein simulates IL-15 in the context of its combined expression with IL-15 Rα by antigen-presenting cells and NK cells or CD8-positive T lymphocytes expressing the CD122 and CD132 receptor complex to increase NK and CD8 T lymphocyte activation and proliferation [28,29]. The role of N-803 as an HIV latency-reversing agent is being evaluated in a phase 2 clinical trial of HIV persistence in acutely infected patients (NCT04505501) [28]. The randomized, controlled trial investigates the safety, tolerability, and immunomodulation effect of combining N-803 and ART with ART alone [29].

Although there have been remarkable advances in antiretroviral therapy to treat HIV infection, there is increasing awareness that persistent and latent reservoirs of HIV-infected cells remain the main barrier to curing HIV infection [29,30]. These reservoirs of HIV-infected cells represent an important mechanism of resistance to antiretroviral therapy in patients with HIV/AIDS [30]. A promising recent strategy to eliminate or reduce this latent reservoir of HIV-infected cells is via the cytokine IL-15 or its superagonist, N-803 (Anktiva), alone or combined with other treatments [30]. N-803 (Anktiva) is an IL-15 superagonist consisting of an N72D mutant IL-15 molecule attached to the alpha receptor and a human IgG1 fragment, which increases IL-15 activity [31]. Preclinical studies have shown that N-803 (Anktiva) reduces HIV reservoirs by activating latent virus to enhance immune effector function [31]. In 2022, a phase 1 study of N-803 in patients with HIV assessed the safety and tolerability of N-803 (Anktiva) in patients with HIV (NCT02191098) [31]. N-803 was associated with the proliferation and activation of CD4-positive and CD8-positive T cells and natural killer (NK) cells (NCT02191098) [31]. These early findings support that approaches such as N-803 (Anktiva) treatment in ART-suppressed people living with HIV should continue, including more extensive clinical trials, as an approach to eliminate HIV reservoirs and progress future hopes for a cure for HIV/AIDS [31]

As of early 2024, the GlobalData Pharmaceutical Intelligence Centre and the HIV Prevention Trials Network reported that more than 900 ongoing and planned clinical trials on HIV were ongoing [32]. However, in 2023, the Thai Red Cross AIDS Research Centre phase 2 trial of N-803 (Anktiva) to reduce HIV persistence in lymph nodes in acute HIV infection failed to show conclusive results (NCT04505501) [33]. The research center is investigating how the candidate reduces HIV persistence in lymph nodes by N-803 (Anktiva) in acute HIV infection and the effect of combining N-803 with N-803 (Anktiva) [33].

People living with HIV are more likely to develop tuberculosis [34]. There is only one prophylactic tuberculosis vaccine, the Bacillus Calmette-Guérin (BCG) vaccine, produced more than 100 years ago and has limited efficacy in the immune-suppressed and elderly [34,35]. MTBVAC is the first live attenuated vaccine to prevent Mycobacterium tuberculosis (M. tuberculosis) infection [36]. The vaccine is derived from the M. tuberculosis isolate MT103, which belongs to one of the most widespread lineages of M. tuberculosis and contains two stable virulence gene deletion mutations without antibiotic resistance [36]. MTBVAC is the first live attenuated M. tuberculosis vaccine approved for use in clinical trials, beginning with a successful first-in-human clinical trial in healthy adults reported in 2015 (NCT02013245) [37]. Currently, the HIV Vaccine Trials Network and the National Institute of Allergy and Infectious Diseases (NIAID) are conducting a phase 2a clinical trial of MTBVAC-01 in patients with and without HIV living in South Africa to investigate the safety and immunogenicity of the vaccine, with a scheduled completion date of November 2024 (NCT05947890) [38].

Conclusions

At the end of each of the four decades that the world has been living with HIV/AIDS, there have been reviews of the progress in achieving effective vaccines and cures for HIV infection. It is possible that by the end of the next decade, developments in vaccine technology and new approaches to preventing retroviral treatment resistance, HIV latency, and reactivation could realize these goals and make the elimination of HIV a future possibility.