Alberta scientists study incomplete immunologic recovery in some people with HIV who have viral suppression

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CATIE News 03122026
  • The ratio of CD4+ to CD8+ blood cells is one marker of immune health in people living with HIV 
  • Among some people on effective HIV treatment, this ratio does not always return to normal
  • An Alberta study of 2,179 people identified underlying factors that contribute to a lower ratio 

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In 1981, doctors in the United States reported increasing numbers of people with severe, sometimes life-threatening infections with no obvious underlying cause. This condition was later named AIDS (acquired immunodeficiency syndrome). In that era, many affected people were young gay and bisexual men whose levels of T cells were mysteriously depleted. By 1983, scientists at the Pasteur Institute in Paris had isolated a virus that is now called HIV. A critical aspect of HIV infection is that this virus directly and indirectly attacks T cells, specifically a subgroup called CD4+ T cells. 

Types of cells and ratios

There are two main types of T cells, as follows:

  • CD4+ cells – this subgroup of T cells helps to link different parts of the immune system and coordinate the response against infections. As HIV attacks these cells, the decline in numbers of CD4+ cells in the blood is closely associated with the decline of the immune system and the risk of life-threatening infections. Monitoring CD4+ cell levels is an important aspect of assessing the effectiveness of HIV treatment (antiretroviral therapy; ART). 
  • CD8+ cells – this subgroup of T cells can directly attack viruses and other microbes, infected cells and cancers. 

In untreated HIV infection, the functioning of these cells is gradually degraded. Levels of CD4+ cells decrease and levels of CD8+ cells increase over the course of infection. What’s more, CD8+ cells become increasingly dysfunctional.

Impact of ART, chronic HIV and inflammation

When used as directed, ART has a tremendous impact on the immune system. Most importantly, ART suppresses the production of HIV by infected cells. As HIV levels fall, the immune system begins to recover. CD4+ cell counts rise, often reaching the normal range; and, to some extent, levels of CD8+ cells begin to fall to within the normal range. These changes greatly reduce the risk of AIDS-related infections. The long-term effect of ART is so profound that many ART users are living into their senior years in generally good health. 

Although ART has many benefits, scientists have found subtle defects in the immune systems of ART users. The immune system remains chronically activated despite HIV having been brought under control by ART. There is also excess inflammation within the immune system. The reason for these findings is not clear. However, it is likely that both chronic inflammation and continued immune activation make it difficult for the immune system to rid itself completely of HIV. 

The reservoir and chronic inflammation

Effective treatment makes HIV undetectable in the blood and benefits the overall health of the individual. What’s more, well-designed studies have found that having an undetectable viral load means that HIV cannot be passed on to sexual partners. However, despite good adherence to ART, small amounts of HIV remain deep within CD4+ cells in tissues such as the lymph nodes, spleen, brain, the lymphoid tissues around the intestines, and so on. Scientists refer to this residue of HIV as the reservoir. 

This chronic burden of HIV-infected cells likely means that from time to time small amounts of HIV-related proteins are released into circulation. These proteins likely contribute to the persistence of subtle immunological defects that have been found in people with HIV. 

What’s more, over the long term, chronic inflammation within the immune system likely contributes to inflammation within other tissues. This can happen because cells of the immune system are distributed around the body in different organs and tissues where they help to defend the body from invading microbes. However, this wide distribution of the immune system’s cells means that if they are activated and inflamed, they release chemical signals that incite inflammation in the tissues and organs that they are patrolling. Chronic inflammation could in theory contribute to an increased risk for the following conditions:

  • high blood pressure
  • pre-diabetes and diabetes
  • abnormal levels of cholesterol
  • chronic kidney disease
  • thinning bones
  • depression
  • muscle weakness
  • degenerative conditions that affect the brain
  • some forms of cancer

Scientists have also found suggestions of premature aging in the immune systems of some ART users.

Despite these complex findings and implications, it is still important for people with HIV to continue to engage in care, initiate ART as soon as possible after diagnosis, and achieve and maintain an undetectable viral load. As mentioned earlier, by keeping HIV suppressed, many ART users can have near-normal life expectancy.

Scientists are working on different ways to try to reduce the burden of the reservoir and ultimately cure HIV infection.

The CD4/CD8 ratio

Many ART users will have increased CD4+ cell counts because of suppressed levels of HIV. What’s more, some ART users may even have CD4+ counts that rise into the normal range—500 cells/mm3 or higher. However, despite these favourable changes, some studies have found that a measure of the immune system’s overall health—the CD4/CD8 ratio—is not necessarily normalized. In people with a healthy immune system, the ratio is 1.0 or greater. However, in people with untreated HIV (or who do not have HIV but have cancer), the ratio is generally less than 1.0. 

Studies in people with HIV have found that less-than-ideal CD4/CD8 ratios are associated with an increased risk for several complications, including the following:

  • cardiovascular disease
  • gastrointestinal diseases
  • kidney-related complications
  • some cancers

A study in Alberta

To better understand changes in the immune systems of ART users, a team of scientists at the University of Calgary and the Southern Alberta HIV Clinic conducted a study. The team focused on the CD4/CD8 ratio in people with HIV who had a suppressed viral load due to ART. The researchers were interested in finding factors that could help explain why some people’s CD4/CD8 ratios do not normalize despite prolonged use of ART.

The researchers analyzed health-related information collected from 2,179 people with HIV between January 1998 and June 2022—a span of 24 years. On average, participants were in the study for a decade. According to the research team, most participants were cisgender males and White and disclosed that they were either gay/bisexual or heterosexual. The proportion of people who injected drugs was relatively low. At the time they entered the study, participants had an average CD4+ count of 257 cells/mm3 and their average age was 35 years.

Recovery of CD4+ cell counts

Age

The researchers found that participants who entered the study at age 51 and older were 41% less likely to achieve a CD4+ count that rose to at least 500 cells/mm3. Participants under the age of 30 were more likely to achieve normalization of their CD4+ cell count. This finding is not surprising. The immune system degrades slightly with each passing year in adults, and younger adults generally would have had a more robust immune system than older adults. Previous studies have found that people who initiated ART at an older age were less likely than younger people to achieve a high CD4+ count.

Sex

The researchers found that cisgender females were 42% more likely than cisgender males to have normalization of their CD4+ cell counts. Previous studies have suggested that the relative balance of estrogen in females (this hormone has anti-inflammatory effects) may help their immune systems better recover their CD4+ counts when ART is used.

Having a high CD4+ count at the start of the study

People who entered the study with higher CD4+ counts (though less than 500 cells/mm3) were more likely to eventually achieve at least 500 CD4+ cells/mm3 compared to people who entered the study with relatively low CD4+ counts.

Other factors

Other factors such as race/ethnicity, year that they entered the study, and HIV risk factors did not have an impact on CD4+ count normalization.

Factors affecting the CD4/CD8 ratio

As mentioned earlier, a well-functioning immune system should have a CD4/CD8 ratio of at least 1.0. 

Age

The researchers found that people aged 50 and older when they entered the study were less likely to achieve a normalized CD4/CD8 ratio than people who were younger than 30 years old when they entered the study. 

African ancestry

People who were of African descent had their chances of achieving a normalized CD4/CD8 ratio reduced by 27% compared to people who were White. One possible reason for this is that Black people in the present study were more likely than White people to be coinfected with a virus called cytomegalovirus. More information about this virus appears later in this bulletin.

Before and after 2007

People who entered the study in 2007 or later were more likely to achieve CD4/CD8 normalization than people who entered the study prior to 2007.

There are several reasons that may explain this finding, including at least the following:

  • ART regimens available in 2007 or later were more effective at suppressing HIV than combinations of drugs used in the past.
  • ART regimens tended to be better tolerated and simpler than in the past.
  • ART may have been initiated earlier in the course of HIV infection than it was in the past.

These factors could have contributed to better adherence by participants, which could also explain the improved likelihood of higher CD4/CD8 ratios.

Having a high CD4+ count at the start of the study

People who entered the study with a relatively high CD4+ count (500 cells/mm3 or greater) were more likely to achieve a normalized CD4/CD8 ratio than people who entered the study with a lower CD4+ count. 

Having a high CD4/CD8 ratio at the start of the study

In general, people who entered the study with a CD4/CD8 ratio of greater than 0.3 were more likely to achieve a normalized ratio.

The researchers found that “the longer [participants] were living with a known HIV diagnosis and had not achieved a CD4/CD8 ratio of 1.0 or greater, the less likely it was that they would achieve this during the study period.”

CMV – A viral passenger

A virus called cytomegalovirus (CMV) is commonly found in adults, including many of those with HIV. It is a member of the herpes family of viruses. It is difficult for the immune system to clear CMV once infection has occurred, so it becomes chronic. Studies in people without HIV suggest that CMV infection is associated with premature aging of the immune system. 

The Alberta researchers found that people who were coinfected with CMV were nearly 50% less likely to achieve a normalized CD4/CD8 ratio than people who were not coinfected with this virus.

Other studies in Canada suggest that CMV coinfection in people with HIV likely plays a role in subtly weakening the immune system and affecting recovery of the CD4/CD8 ratio.

Type of ART

Today, most anti-HIV drugs used to anchor a treatment regimen belong to the following classes of medicines (with commonly used examples):

  • integrase inhibitors – bictegravir, cabotegravir, dolutegravir
  • protease inhibitors – darunavir
  • non-nukes – rilpivirine, doravirine, efavirenz

The Alberta researchers found that no particular class of anti-HIV medicines affected the CD4/CD8 normalization. 

Bear in mind

The present study is important because of its long duration of monitoring. Its findings are relevant to the Canadian population. It found that CMV coinfection is likely one factor that impedes the recovery of the immune system despite good adherence to ART in some people. 

There may be other factors that can affect immunological recovery, including at least the following:

  • an imbalance of bacteria in the gut
  • weakened integrity of the lining of the gut; this could allow bacteria and their toxins to enter the body and incite inflammation and immune activation
  • inflammatory conditions such as Crohn’s and colitis
  • additional coinfections such as chronic hepatitis B virus (HBV)
  • low-level release of HIV proteins from infected cells
  • late diagnosis and initiation of HIV treatment

This study underscores the importance of timely HIV testing, diagnosis and initiation of treatment.

Research on helping more ART users normalize their CD4/CD8 ratios could lead to better health in this population and a reduced risk for comorbidities over time. 

Scientists are proposing different ways to try to reduce the excess immune activation and inflammation that accompanies chronic HIV infection despite the use of ART. 

Find out more about some of these clinical trials on the website of CTN+ (CIHR Pan-Canadian Network for HIV and STBBI Clinical Trials Research).

—Sean R. Hosein

Resources

CTN+

North American study finds low CD4/CD8 ratio can help predict cancer risk in people with HIV – CATIE News

Ontario study links low T-cell counts to increased risk for certain cancers in people with HIV – CATIE News

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