Microscopic view of HIV-infected cells in the gut with a CD4+ T cell count indicator.

HIV Reservoir: The CD4 Count Connection to Viral Control

Lena Kashyap in Health & Wellness December 2025 • 4 min read.

"Discover how early cART intervention, guided by CD4 counts, shapes viral reservoir size and immune health in HIV-1 infected patients."

For individuals living with HIV, combined antiretroviral therapy (cART) has marked a significant leap forward, dramatically enhancing the quality of life and extending lifespans. Yet, despite its effectiveness in suppressing the virus, cART falls short of completely eradicating viral reservoirs. These reservoirs, particularly those in the gut-associated lymphoid tissue (GALT), continue to pose a challenge in achieving a complete cure.

The gut-associated lymphoid tissue (GALT) is the largest reservoir of HIV-1, harboring a significant number of HIV target cells, including activated memory CD4+/CCR5+ T cells. These intestinal T and B cells express α4β7 integrin, a gut mucosal homing receptor that binds to gp120 HIV-1 envelope, facilitating the infection of intestinal T cells and the establishment of the gut HIV reservoir.

New research investigates how the timing of cART initiation, specifically considering CD4+ T cell counts, influences the constitution of viral and immunological reservoirs in the rectum of HIV-1 infected patients undergoing long-term treatment. This study sheds light on potential strategies for improving immune reconstitution and viral control.

How Does CD4 Count at cART Initiation Affect Viral Reservoir Size?

Microscopic view of HIV-infected cells in the gut with a CD4+ T cell count indicator.

The study, published in Retrovirology, divided twenty-four consenting men into two groups based on their CD4+ T cell counts at the start of cART. Nine participants had CD4+ T cell counts above 350/mm³ (high-level CD4 group), while fifteen had counts below this threshold (low-level CD4 group). Researchers then performed a detailed immunophenotypical analysis of T and B cell subpopulations in both blood and rectal biopsies to determine HIV cell-associated DNA loads and intracellular RNA.

Key findings revealed significant differences between the two groups, including the:

Ratio of CD4+/CD8+ T cells: Significantly decreased in the blood but not in the rectum of the “low-level CD4 group.”
β7+ CD4+ T cells homing: Alteration was higher in the “low-level CD4 group” and correlated with a low CD4+/CD8+ T cell ratio in blood.
B cell maturation: Initiation of cART with a low-level CD4 count was associated with an alteration in B cell maturation.
HIV DNA reservoirs: Both blood and gut HIV DNA reservoirs were significantly lower in the “high-level CD4 group.” A high HIV DNA level was associated with detectable intracellular HIV RNA in the rectum.

These results indicate that initiating cART at an earlier stage of HIV infection, when CD4+ T cell counts are higher, may help preserve gut immunity and limit the establishment and size of the viral reservoir. The study underscores the importance of early diagnosis and intervention in managing HIV-1 infection.

The Future of HIV Treatment: Focus on Early Intervention

The study’s conclusion emphasizes that early initiation of cART can significantly preserve gut immunity and limit viral reservoir constitution, reinforcing the importance of early diagnosis and treatment. As research continues, future strategies may focus on refining cART regimens and timing to optimize immune reconstitution and achieve better long-term control of HIV infection. These insights offer hope for improving outcomes and potentially moving closer to a functional cure.

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This article is based on research published under:

DOI-LINK: 10.1186/s12977-016-0278-5, Alternate LINK

Title: Major Influence Of Cd4 Count At The Initiation Of Cart On Viral And Immunological Reservoir Constitution In Hiv-1 Infected Patients

Subject: Infectious Diseases

Journal: Retrovirology

Publisher: Springer Science and Business Media LLC

Authors: Anne-Emmanuelle Depincé-Berger, Delphine Vergnon-Miszczycha, Alexandre Girard, Anne Frésard, Elisabeth Botelho-Nevers, Claude Lambert, Emilie Del Tedesco, Christian Genin, Bruno Pozzetto, Frédéric Lucht, Xavier Roblin, Thomas Bourlet, Stéphane Paul

Published: 2016-06-30

Everything You Need To Know

What role does the CD4 count play in the context of HIV treatment?

The CD4 count is a measure of the number of CD4+ T cells in the blood. These cells are crucial components of the immune system that are targeted and destroyed by HIV-1. This study found that initiating combined antiretroviral therapy (cART) when the CD4 count is higher results in smaller HIV reservoirs and better preservation of gut immunity. A higher CD4 count at the start of cART indicates that the immune system is in a better state to begin with. Early intervention with cART, guided by the CD4 count, can improve the immune response and ultimately, patient outcomes.

What is combined antiretroviral therapy (cART) and why is it important in managing HIV?

Combined antiretroviral therapy (cART) is a treatment approach that has revolutionized HIV management, significantly improving the quality of life and extending lifespans for individuals living with HIV-1. cART works by suppressing the replication of HIV-1 in the body. However, while cART is highly effective at controlling the virus, it does not completely eradicate HIV-1. The virus can persist in reservoirs, such as the gut-associated lymphoid tissue (GALT), which continue to pose a challenge. The timing of when cART is initiated is critical to its effectiveness in long-term control of HIV infection.

Why is the gut-associated lymphoid tissue (GALT) significant in HIV infection?

The gut-associated lymphoid tissue (GALT) is the largest reservoir for HIV-1 in the body. It contains a significant number of HIV target cells, including activated memory CD4+/CCR5+ T cells. The GALT is important because it is a primary site where the virus establishes itself and persists. The gut's immune environment, with its unique cell populations and homing receptors, provides a favorable environment for HIV-1 to hide and replicate. This makes the GALT a critical area to target for effective HIV treatment and the potential for a cure.

How did the researchers in the study differentiate the groups of participants?

The study divided participants into two groups based on their CD4+ T cell counts at the start of combined antiretroviral therapy (cART). The “high-level CD4 group” had counts above 350/mm³, and the “low-level CD4 group” had counts below this threshold. The researchers then analyzed differences in immune cell populations and viral loads. They found that the “high-level CD4 group” had significantly lower HIV DNA reservoirs in both blood and gut, highlighting the benefits of starting cART earlier in the course of HIV infection, when the CD4 count is higher.

What are the implications of initiating combined antiretroviral therapy (cART) based on CD4 counts?

Early initiation of combined antiretroviral therapy (cART), based on CD4 count, can help preserve gut immunity and limit the establishment and size of the viral reservoir. The study indicates that starting cART when CD4+ T cell counts are higher is associated with better immune reconstitution and viral control. This involves a decreased ratio of CD4+/CD8+ T cells, alterations in β7+ CD4+ T cells, changes in B cell maturation, and lower HIV DNA reservoirs. These findings underscore the importance of early diagnosis and intervention in managing HIV-1 and moving towards improved long-term outcomes and a possible functional cure.