How Genital Shedding Increases HIV Risk

Transmission possible even with undetectable virus

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If you are on HIV therapy and taking your drugs as prescribed, you would think that your risk of passing the virus to others would be low, right?

In most cases, you would be correct, but there are instances when persons with an undetectable viral load in their blood suddenly have detectable virus in their semen or vaginal secretions. This is a phenomenon known as viral shedding. While we mostly refer to shedding when it happens in the male or female genital tract (genital shedding), it can also occur in the mouth (oral shedding).

An increase in viral activity—particularly in semen or vaginal secretions—translates to a greater potential for HIV transmission to an uninfected partner.

How Genital Tract Shedding Occurs

In scientific terms, the word "shedding" refers to the process where a virus is released, or shed, from the host cell it has infected. Two of the ways this can happen are through processes known as budding and apoptosis:

  • Budding refers to a stage in the HIV life cycle where the virus scavenges membrane from a cell it has infected to create its own outer shell. It can then bud from the host as a free-circulating virus.
  • Apoptosis, also known as cell suicide, is the process where a cell will kill itself when placed under stress. During a typical infection, apoptosis will destroy an invading virus along with the host cell itself. With HIV, however, the virus will force a cell into apoptosis in order to release its offspring into circulation.

    What neither of these things explains is why HIV shedding can occur in the genital tract but not in blood where it might otherwise be fully undetectable.

    Evidence now suggests that two factors may contribute to this: the variability of HIV within the cells of our body and the variability of HIV drug concentrations within the tissues of our body.

    Genital Tract Shedding and HIV Variability

    One of the earliest revelations took place in 2000 when it was discovered that the strain of HIV can vary from one part of the body to the next. According to research from the long-standing Multicenter AIDS Cohort Study (MACS), some individuals with HIV were shown to have one genetic variation of the virus in their blood and another in their semen.

    The study further looked into the patterns of shedding among research participants. In some cases, shedding was a continuous process occurring in both the blood and semen. In others, it was intermittent and took place primarily in the genital tract. In others still, there was no shedding at all.

    What these findings suggested was that:

    • The variability of the HIV could translate to differing responses to therapy.
    • HIV shedding may be a condition to which a person is genetically predisposed.

    Of those persons experiencing intermittent shedding, the findings were even profound. Of these men, the MACS investigators noted that bacterial infections of the prostate gland were closely aligned with spikes in viral activity in semen. They hypothesized that localized inflammation of the prostate (the organ which produces semen) triggered shedding by activating dormant viruses embedded in the cells of the prostate gland and seminal vesicles.

    Subsequent studies have largely supported these findings and have shown that shedding can occur as a direct result of sexually transmitted infections (STIs), coexisting diseases, and even menstruation.

    Effectiveness of HIV Drugs Can Vary in Blood, Tissues

    We test blood for HIV not because it is the best measure for infection but because it offers the easiest access when compared to, say, bone marrow or tissue samples. That’s not to say that it’s not an extremely strong measure—it is—but it doesn’t necessarily provide us the full picture in how effectively antiretroviral drugs penetrate the different cells and tissues of our body.

    We have long known, for example, that drugs like zidovudine (AZT) are able to infiltrate brain and spinal cells more effectively and at higher concentrations than almost all other HIV drugs. This is why it had been long used in people with AIDS dementia complex as a means to slow progression of the disease.

    Similarly, there is growing evidence the drug Truvada, when used as a prevention therapy (known as PrEP), does not penetrate vaginal tissue in the same way that it does the rectum.

    Research from the University of North Carolina at Chapel Hill showed that Truvada concentration in rectal tissue could offer upwards of 90 percent protection with only two to three PrEP doses per week. By contrast, the concentration of Truvada in vaginal tissue was far lower, providing only 70 percent protection even with near-perfect daily adherence.

    The same could very well apply to the male genital tract. If so, it is possible that HIV therapy can suppress the virus elsewhere in the body but fall short in the genital tract if there is an infection.

    In this case, it is believed that immune system could very well be the trigger that sparks shedding in both males and females.

    How Your Immune System Triggers Shedding

    The presence of any infection will activate the immune system. When this happen, the body will respond by releasing substances in the body called cytokines which serve to signal and direct immune cells to the source of the infection. While some of these cytokines help fight disease, other have a contradictory effect by "waking" dormant HIV hidden in various cells and tissues of the body.

    Known as latent reservoirs, these cellular havens effectively shield HIV from the body’s immune defenses. It is often during an acute illness, when the immune system is activated, that the virus will suddenly re-emerge. This is why some people can go for years without treatment and then suddenly have a major illness accompanied by an enormous spike in viral activity.

    The same pattern seems to apply to the genital tract shedding of HIV. In the presence of an infection, say an STI or prostatitis, the immune system will release a distinct array of proinflammatory cytokines (the type associated with inflammation). This sudden burst of localized inflammation is directly linked to an increase in viral shedding.

    When this happens, defensive white blood cells (leukocytes) will suddenly flood the site of infection. One such leukocyte, called a CD4 T-cell, is the primary target of HIV. As these T-cells are infected in the early attack, the viral numbers rise until such time as the localized infection is brought under control.

    It is during this burst of viral activity that a person on HIV treatment can potentially pass the virus to others. While the viral load may increase by only one log or so (jumping from, say, 100 to 1,000), it may still be enough to facilitate infection.

    HIV Shedding During Menstruation

    Genital shedding of HIV can occur as a result of menstruation. While shedding may not significantly increase transmission risk from women on HIV therapy, it can in those who are either unaware of their status or have not been treated.

    A study from the Oregon Health and Science University (OSHU) investigated a group of women of who were predisposed to genital shedding as a result of a coexisting herpes simplex (HSV-2) infection. (HSV-2, a virus affecting 67 percent of the world’s population, is also known to cause vaginal shedding both in symptomatic and asymptomatic women.)

    Within this group of women, HIV shedding was common during menstruation with a nearly eight-fold increase in viral load compared to the premenstrual cycle. This happened whether a woman had symptoms of HSV-2 or not. While this increase may not represent much in women with suppressed viral activity, it was considered significant in those with higher viral loads.

    According to the researchers, viral shedding during menstruation could mean as much as a 65 percent increase in HIV risk if a woman is untreated. By contrast, HIV therapy can minimize, although not entirely erase, risk to an infected male partner.

    A Word From Verywell

    Since the introduction of PrEP, we’ve seen a measurable drop in the use of condoms. One French study, in fact, showed that the more consistently a person took PrEP, the less likely he or she would be to use condoms (54 percent less likely to be exact).

    While the effectiveness of PrEP is doubtless, particularly in mixed-status couples and persons at high-risk of infection, it shouldn’t suggest that condoms are any less important than they ever were.

    Ultimately, any HIV infection is a result of multiple factors including, among other things, the type of sexual activity involved and the general health of the uninfected individual. Even if the viral load of the infected person is low, other factors can mount one on top of the next to increase that risk, sometimes significantly.

    An undiagnosed STI paired with bacterial vaginosis paired with a nominal spike in viral activity is sometimes all it takes to turn a "low-risk" sexual activity into an opportunity for infection.

    If in doubt about your sexual partner, and if you have multiple sexual partners, don’t take a chance. Use condoms and any other tools of prevention to protect yourself and your partner.

    Sources:

    Gupta, P.; Leroux, C.; Patterson, B.; et al. "Human Immunodeficiency Virus Type 1 Shedding Pattern in Semen Correlates with the Compartmentalization of Viral Quasi-Species between Blood and Semen." Journal of Infectious Diseases. 2000: 182;79-87.

    Patel, E.; Kirkpatrick, A.; Grabowski, M.; et al. "Penile Immune Activation and Risk of HIV Shedding: A Prospective Cohort Study." Clin Infect Dis. 2017; 64(6):776-784.

    Spencer, L.; Christiansen, S.; Wang, C. "Systemic Immune Activation and HIV Shedding in the Female Genital Tract." Journal of Acquired Immune Deficiency Syndromes. 2016; 71(2):155-162.

    Cottrell, M.; Yang, K.; Prince, H.; et al. "Predicting effective Truvada PrEP dosing strategies with a novel PK–PD model incorporating tissue active metabolites and endogenous nucleotides (EN)." HIV Research for Prevention Conference; Cape Town, South Africa; October 28-31 2014; oral abstract 22.06 LB.

    Teyssier, L.; Suzan-Monti, M.; Castro, D. "PrEP and Condom Use in High-Risk MSM in the ANRS IPERGAY Trial." Conference on Retroviruses and Opportunistic Infections (CROI); Boston, Massachusetts; February 22-25, 2016; abstract 887.

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