Logo Medical Science Monitor

Call: +1.631.470.9640
Mon - Fri 10:00 am - 02:00 pm EST

Contact Us

Logo Medical Science Monitor Logo Medical Science Monitor Logo Medical Science Monitor

01 April 2024: Editorial  

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

Dinah V. Parums1A*

DOI: 10.12659/MSM.944600

Med Sci Monit 2024; 30:e944600




ABSTRACT: 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 became known as human immunodeficiency virus (HIV) in 1986. For the past 40 years, prevention and cure of HIV infection have been the dual ‘holy grail’ sought but still not achieved. By the beginning of 2024, the World Health Organization (WHO) estimated that in the past 40 years, between 65.0 million and 113.0 million people have been infected with HIV, and between 32.9 million and 51.3 million people have died from HIV infection. On 29 February 2024, the WHO published an updated report in response to increasing reports of HIV drug resistance (HIVDR). Currently, HIV vaccines in development are in early-stage clinical trials. People with HIV are more likely to develop tuberculosis, with increasing rates of antimicrobial resistance. MTBVAC is the first live attenuated vaccine to prevent Mycobacterium tuberculosis infection, with phase 2a safety and efficacy clinical trial data expected at the end of 2024. This editorial aims to summarize the current challenges and hopes for developing vaccines to prevent HIV infection and approaches to overcome antiretroviral drug resistance as a cure for HIV/AIDS.

Keywords: Editorial, HIV, human immunodeficiency virus, vaccine, Tuberculosis

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].


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.


1. Barré-Sinoussi F, Chermann JC, Rey F, Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS): Science, 1983; 220(4599); 868-71

2. Gallo RC, Salahuddin SZ, Popovic M, Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS: Science, 1984; 224(4648); 500-3

3. Broder S, Gallo RC, A pathogenic retrovirus (HTLV-III) linked to AIDS: N Engl J Med, 1984; 311(20); 1292-97

4. Marx JL, AIDS virus has new name – perhaps: Science, 1986; 232(4751); 699-700

5. World Health Organization (WHO), The Global Health Observatory: HIV, 2024 Available from: https://www.who.int/data/gho/data/themes/hiv-aids

6. Barré-Sinoussi F, Ross AL, Delfraissy JF, Past, present and future: 30 years of HIV research: Nat Rev Microbiol, 2013; 11(12); 877-83

7. Cummins NW, Badley AD, Can HIV be cured and should we try?: Mayo Clin Proc, 2015; 90(6); 705-9

8. Fischer W, Giorgi EE, Chakraborty SNetwork for genomic surveillance in South Africa (NGS-SA); et al, HIV-1 and SARS-CoV-2: Patterns in the evolution of two pandemic pathogens: Cell Host Microbe, 2021; 29(7); 1093-110

9. Bell LCK, Noursadeghi M: Nat Rev Microbiol, 2018; 16(2); 80-90

10. Parums DV, Editorial: Updates from the World Health Organization (WHO) on global treatment recommendations for drug-susceptible and multidrug-resistant tuberculosis: Med Sci Monit, 2021; 27; e934292

11. Mu Z, Haynes BF, Cain DW, HIV mRNA vaccines-progress and future paths: Vaccines (Basel), 2021; 9(2); 134

12. Parums DV, Editorial: mRNA vaccines and future epidemic, pandemic, and endemic zoonotic virus infections: Med Sci Monit, 2021; 27; e932915

13. Berkley S, The international AIDS vaccine initiative: J Int Assoc Physicians AIDS Care, 1997; 3(11); 30-34

14. : International AIDS Vaccine Initiative (IAVI) statement on mRNA HIV vaccine candidate trials March 2, 2024 Available from: https://www.iavi.org/features/iavi-statement-on-mrna-hiv-vaccine-candidate-trials/

15. Abbasi J, First mRNA HIV vaccine clinical trial launches: JAMA, 2022; 327(10); 909

16. National Institutes of Health (NIH), News release. Experimental HIV vaccine regimen safe but ineffective, study finds: The clinical trial began in 2019 and involved 3,900 volunteers January 18, 2023 Available from: https://www.nih.gov/news-events/news-releases/experimental-hiv-vaccine-regimen-safe-ineffective-study-finds

17. Stieh DJ, Barouch DH, Comeaux CASCENT/HVTN118/HPX2003 Study Team, Safety and immunogenicity of Ad26-vectored HIV vaccine with mosaic immunogens and a novel mosaic envelope protein in HIV-uninfected adults: A Phase 1/2a Study: J Infect Dis, 2023; 227(8); 939-50

18. Haynes BF, Wiehe K, Borrow P, Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies: Nat Rev Immunol, 2023; 23(3); 142-58

19. Smith SJ, Zhao XZ, Passos DO, Integrase strand transfer inhibitors are effective anti-HIV drugs: Viruses, 2021; 13(2); 205

20. World Health Organization (WHO), Factsheet: HIV and AIDS July 13, 2023 Available from: https://www.who.int/news-room/fact-sheets/detail/hiv-aids

21. World Health Organization (WHO): HIV drug resistance-brief report 2024 Feb 29, 2024 Available from: https://iris.who.int/bitstream/handle/10665/376039/9789240086319-eng.pdf

22. Deeks SG, Archin N, Cannon PInternational AIDS Society (IAS) Global Scientific Strategy working group, Research priorities for an HIV cure. International AIDS Society Global Scientific Strategy 2021: Nat Med, 2021; 27(12); 2085-98

23. Sista ND, Abdool Karim Q, Hinson K, Experience in international clinical research: the HIV Prevention Trials Network: Clin Investig (Lond), 2011; 1(12); 1609-18

24. : HIV Prevention Trials Network (HPTN), 2024 Available from: https://www.hptn.org/about#

25. Maciel M, Amara RR, Bar KJ, Exploring synergies between B- and T-cell vaccine approaches to optimize immune responses against HIV-workshop report: NPJ Vaccines, 2024; 9(1); 39

26. Bonnard D, Le Rouzic E, Singer MR, Biological and structural analyses of new potent allosteric inhibitors of HIV-1 integrase: Antimicrob Agents Chemother, 2023; 67(7); e0046223

27. Lichterfeld M, Gao C, Yu XG, An ordeal that does not heal: understanding barriers to a cure for HIV-1 infection: Trends Immunol, 2022; 43(8); 608-16

28. Xu W, Jones M, Liu B, Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor αSu/Fc fusion complex in syngeneic murine models of multiple myeloma: Cancer Res, 2013; 73(10); 3075-86

29. Duan S, Liu S, Targeting NK cells for HIV-1 treatment and reservoir clearance: Front Immunol, 2022; 13; 842746

30. Howard JN, Bosque A, IL-15 and N-803 for HIV cure approaches: Viruses, 2023; 15(9); 1912

31. Miller JS, Davis ZB, Helgeson E, Safety and virologic impact of the IL-15 superagonist N-803 in people living with HIV: A phase 1 trial: Nat Med, 2022; 28(2); 392-400

32. Donnell D, Kansiime S, Glidden DV, Study design approaches for future active-controlled HIV prevention trials: Stat Commun Infect Dis, 2024; 15(1); 20230002

33. Wang YS, Kumari M, Chen GH, mRNA-based vaccines and therapeutics: An in-depth survey of current and upcoming clinical applications: J Biomed Sci, 2023; 30(1); 84

34. Bruchfeld J, Correia-Neves M, Källenius G, Tuberculosis and HIV coinfection: Cold Spring Harb Perspect Med, 2015; 5(7); a017871

35. Pollard AJ, Bijker EM, A guide to vaccinology: From basic principles to new developments: Nat Rev Immunol, 2021; 21(2); 83-100

36. Arbues A, Aguilo JI, Gonzalo-Asensio J: Vaccine, 2013; 31(42); 4867-73

37. Spertini F, Audran R, Chakour R: Lancet Respir Med, 2015; 3(12); 953-62

38. da Costa C, Benn CS, Nyirenda T, Perspectives on development and advancement of new tuberculosis vaccines: Int J Infect Dis, 2024; 26; 106987

In Press

Clinical Research  

Differential Inflammatory Responses in Adult and Pediatric COVID-19 Patients: Implications for Long-Term Co...

Med Sci Monit In Press; DOI: 10.12659/MSM.944052  

Clinical Research  

Effectiveness of Shoulder Taping in Treating Hemiplegic Shoulder Subluxation: A Randomized Controlled Study...

Med Sci Monit In Press; DOI: 10.12659/MSM.944222  

Clinical Research  

Comparison of Fentanyl, Ketamine, and Lidocaine Combined with Propofol Anesthesia in Patients with Crohn Di...

Med Sci Monit In Press; DOI: 10.12659/MSM.944116  

Database Analysis  

ANXA5: A Key Regulator of Immune Cell Infiltration in Hepatocellular Carcinoma

Med Sci Monit In Press; DOI: 10.12659/MSM.943523  

Most Viewed Current Articles

17 Jan 2024 : Review article  

Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron Variant

DOI :10.12659/MSM.942799

Med Sci Monit 2024; 30:e942799


14 Dec 2022 : Clinical Research  

Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase Levels

DOI :10.12659/MSM.937990

Med Sci Monit 2022; 28:e937990


16 May 2023 : Clinical Research  

Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...

DOI :10.12659/MSM.940387

Med Sci Monit 2023; 29:e940387


01 Jan 2022 : Editorial  

Editorial: Current Status of Oral Antiviral Drug Treatments for SARS-CoV-2 Infection in Non-Hospitalized Pa...

DOI :10.12659/MSM.935952

Med Sci Monit 2022; 28:e935952


Your Privacy

We use cookies to ensure the functionality of our website, to personalize content and advertising, to provide social media features, and to analyze our traffic. If you allow us to do so, we also inform our social media, advertising and analysis partners about your use of our website, You can decise for yourself which categories you you want to deny or allow. Please note that based on your settings not all functionalities of the site are available. View our privacy policy.

Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750