Why HIV Persists in the Body
HIV-1 remains in the body due to a small population of CD4+ memory T cells that harbor viral DNA, or provirus. The virus is dormant in these cells, rendering it undetectable by the immune system and impervious to antiretroviral drugs. These cells constitute the viral reservoir, preventing complete infection eradication.
Can the Viral Reservoir Be Eliminated?
Current antiretroviral drugs prevent HIV replication but do not target latently infected cells, which can persist for a lifetime. The virus carries genetic defects in most cells that prevent its reactivation. However, a small fraction contains a replication-competent virus that may reactivate upon treatment interruption.
Attempts to eliminate the HIV reservoir through pharmacological or immune-based therapies have largely been unsuccessful, except in cases of stem cell transplantation. However, evidence suggests that the immune system can influence the size and dynamics of the viral reservoir, which is particularly evident in elite controllers—individuals who maintain undetectable viral loads without treatment. In these individuals, HIV is often integrated into less accessible genomic regions, potentially due to immune selection, where cells harboring actively replicating viruses are eliminated, leaving only those where HIV remains dormant. Similar patterns of immune-driven selection have been observed in patients undergoing long-term antiretroviral therapy. The specific immunological mechanisms governing this process remain unclear, but studies suggest a link between innate immunity and viral reservoir dynamics.
Making HIV Susceptible to Immune Attack
One strategy to combat HIV-1 is to force the virus out of latency, rendering it visible to the immune system. This approach utilizes drugs that activate proviral transcription. Histone deacetylase inhibitors (HDACi) have demonstrated the ability to activate HIV in both laboratory and clinical studies transiently. HDACi enhance histone acetylation at specific chromatin sites, making DNA more accessible for transcription and potentially reactivating latent viruses.
While HDACi, in combination with immune-based therapies (vaccines, antibodies), have induced transient increases in plasma viral RNA, they have not significantly reduced the size of the viral reservoir.
Combination Therapy with Panobinostat and Pegylated Interferon-α2a: A Clinical Study
Researchers from the Ragon Institute (USA) investigated a combination therapy for HIV using the HDAC inhibitor panobinostat and PEG-IFN-α2a. Pegylated interferon-α2a has been previously used to treat hepatitis B and C and is known to activate innate immunity. Previous studies have shown that PEG-IFN-α2a can reduce HIV latency, alter reservoir dynamics, and delay viral rebound after treatment interruption.
This combination therapy disrupted HIV latency, activated innate immune cells, and reduced the frequency of intact proviruses. These findings demonstrate that latency disruption via HDACi and innate immune activation can reshape the HIV reservoir, as immune cells preferentially eliminate cells where the virus is integrated into more accessible genomic regions.
Study Design
Seventeen HIV-1-positive individuals on antiretroviral therapy (ART) were assigned to three groups:
- Group A (4 participants) – panobinostat only
- Group B (9 participants) – panobinostat plus PEG-IFN-α2a
- Group C (4 participants) – PEG-IFN-α2a only
Panobinostat was administered orally at 15 mg on days 0, 2, and 4 during the first week. PEG-IFN-α2a was given as a single subcutaneous dose of 180 µg on day 0. ART was maintained throughout the study for all participants.
Peripheral blood mononuclear cells were collected at baseline (day 0), on day 4 (six hours after the final panobinostat dose), and day 28.
Adverse Events
The most common adverse effects among participants receiving PEG-IFN-α2a were body aches and fatigue. Those taking panobinostat most frequently reported nausea and mild diarrhea. One participant receiving combination therapy experienced transient neutropenia. No serious adverse events were reported.
Increased Histone Acetylation and Viral Transcription
After four days of panobinostat treatment, either alone or in combination with PEG-IFN-α2a, histone acetylation levels in CD4+ T cells increased by an average of 4.7-fold. By day 28, histone acetylation returned to baseline. No significant histone acetylation changes were observed with PEG-IFN-α2a alone.
Total HIV-1 RNA levels increased by an average of 1.83-fold in all participants receiving combination therapy, except for one. There were no significant differences in HIV-1 transcription between the panobinostat-only and PEG-IFN-α2a-only groups.
Two participants in group A experienced a sharp increase in plasma viral load, with 25 and 213 copies of HIV-1 RNA/mL detected six hours after the first panobinostat dose. Another participant in group A had a viral spike of 30 copies/mL on day 4, six hours after the final panobinostat dose.
Activation of Innate Immune Responses
Treatment with PEG-IFN-α2a, both alone and in combination with panobinostat, activated innate immunity, enhancing the function of dendritic cells, monocytes, and NK cells while stimulating the expression of genes involved in antiviral defense. The genes most strongly upregulated following PEG-IFN-α2a treatment encoded proteins responsible for pathogen recognition.
Combination Therapy Reduces the Number of Intact Proviruses
The number of defective, replication-incompetent proviruses remained unchanged during treatment. However, the number of intact, replication-competent proviruses decreased by approximately 40% over 28 days, suggesting that cells harboring intact proviruses are more immunologically vulnerable than those containing defective HIV-1 proviruses. NK cells may play a critical role in this process, as their activation on days 0 and 4 coincided with a reduction in the viral reservoir.
Although combination therapy may shrink the active HIV-1 reservoir, it does not affect proviral clones integrated into immune-inaccessible genomic regions. These proviruses may evade immune clearance by producing fewer viral proteins that attract immune cells.
Following treatment, some patients exhibited an increased frequency of provirus integration in less accessible genomic regions, indicating that during therapy, the immune system selectively eliminated cells containing viral sequences in more accessible genomic sites. In contrast, proviruses in transcriptionally silent areas persisted.
Conclusion
Even a short course of combination therapy with panobinostat and PEG-IFN-α2a induced significant changes in the structure and composition of the HIV-1 reservoir. This approach may hold promise, particularly when incorporated into more potent and prolonged treatment regimens. Further research is needed to identify the immune mechanisms that most effectively target infected cells following latency reversal, a crucial step toward an HIV cure.
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