TreatmentUpdate
231

June 2019 

Revisiting HIV co-receptors and their role in cure research

About 10 years ago the world was surprised by the news that a person with HIV had been cured. This person, Timothy Brown, had been treated for life-threatening cancer with two stem cell transplants, intensive rounds of chemotherapy and radiation, and additional suppression of his immune system. The transplant came from a donor with a rare genetic mutation, called delta-32 by scientists. Cells of the immune system from people with this mutation lack a receptor called CCR5—one of the receptors that HIV needs to infect a cell.

Know your receptors and co-receptors

HIV needs two receptors to infect cells of the immune system. These receptors act in the same way a lock functions on a door. Until the door is unlocked, no one, in this case HIV, can enter the room.

The main receptor is called CD4; this is found on many cells of the immune system such as T-cells, macrophages and related cells. After interacting with CD4, HIV then needs to interact with another receptor, usually either one called CCR5 (R5) or CXCR4 (X4). These two other receptors (R5 and X4) are called co-receptors.

In untreated HIV disease, HIV that uses X4 is relatively uncommon because researchers strongly suspect that it is easier for the immune system to find and attack HIV that uses that co-receptor. As a result, HIV that uses the R5 co-receptor is generally more common. However, when AIDS develops, the immune system has been severely injured and is no longer able to find and attack HIV that uses X4. As a result, HIV that uses X4 is more common in people that have severe immune deficiency (AIDS).

In very rare cases, there may even be other co-receptors used by HIV, such as CXCR6. However, because they are so rare, strains of HIV using co-receptors such as CXCR6 are not widely studied.

Genes and people

In general, it appears that HIV-negative people can live a healthy long life without having the R5 co-receptor. People who have the delta-32 mutation that causes this lack of R5 co-receptor are rare. Generally, this mutation is found in less than 1% of people of northern European descent, and it is even rarer in other ethno-racial groups.

The X4 co-receptor is found both within and outside of the immune system:

  • in organs such as the brain and heart
  • in tissues such as nerves and blood vessels

Blocking X4 co-receptors for a prolonged period of time could, in theory, lead to serious problems. About 20 years ago, researchers were testing an experimental drug that could block the X4 co-receptor in HIV-positive people. They halted further development of that drug in this population because of concerns from animal studies that it may cause liver injury. For these and other reasons, the only co-receptor that is largely the focus of HIV treatment or cure research is R5. There is a drug approved for HIV treatment that blocks the R5 co-receptor (maraviroc) but it is not commonly used. Furthermore, its use is not associated with anyone being cured of HIV infection.

Not just any stem cells

The stem cells that are used for HIV cure experiments must come from donors with the rare delta-32 mutation. However, for these transplants to avoid becoming infected with HIV after transplantation, the recipient must first be screened for the possibility of having X4-using strains of HIV. If they harbour X4-using HIV, there is the possibility that residual HIV could infect the transplanted stem cells.

Note that more than a stem cell transplant from a donor with the delta-32 mutation is needed to effect an HIV cure. So far chemotherapy appears to be needed as well. There may be other factors involved, such as something called graft vs. host disease (GvHD)—an immunological reaction that occurs in people who have received transplanted tissue or cells. Later in this issue of TreatmentUpdate we briefly explore the issue of GvHD.

Key points

  • HIV infects cells of the immune system using the CD4 receptor.
  • HIV also needs one other co-receptor, most commonly one called CCR5 (R5) or to a lesser extent, another one called CXCR4 (X4).
  • In rare cases, there is a genetic mutation called delta-32, found in less than 1% of people of northern European ancestry.
  • Stem cell transplants from people with the rare delta-32 mutation are used in some HIV cure experiments.

As we went to press, a report emerged about an analysis of a large database suggesting that some people with the delta-32 mutation (the vast majority of whom are HIV-negative) may have an increased risk for long-term health complications. A future issue of TreatmentUpdate will review this report and its implications for HIV treatment and cure research.

Resources

The Canadian HIV Cure Enterprise (CanCURE)

—Sean R. Hosein

REFERENCES:

  1. Kuritzkes DR. Hematopoietic stem cell transplantation for HIV cure. Journal of Clinical Investigation. 2016 Feb;​126(2):432-7.
  2. Ostrowski MA, Justement SJ, Catanzaro A, et al. Expression of chemokine receptors CXCR4 and CCR5 in HIV-1-infected and uninfected individuals. Journal of Immunology. 1998 Sep 15;161(6):3195-201.
  3. Sheppard HW, Celum C, Michael NL, et al. HIV-1 infection in individuals with the CCR5-Delta32/Delta32 genotype: acquisition of syncytium-inducing virus at seroconversion. JAIDS. 2002 Mar 1;29(3):307-13.
  4. Schuitemaker H, van ‘t Wout AB, Lusso P. Clinical significance of HIV-1 coreceptor usage. Journal of Translational Medicine. 2011 Jan 27;9 Suppl 1:S5.
  5. Lin YL, Portales P, Segondy M, et al. CXCR4 overexpression during the course of HIV-1 infection correlates with the emergence of X4 strains. JAIDS. 2005 Aug 15;39(5):530-6.
  6. Zhang L, He T, Talal A, et al. In vivo distribution of the human immunodeficiency virus/simian immunodeficiency virus coreceptors: CXCR4, CCR3, and CCR5. Journal of Virology. 1998 Jun;72(6):5035-45.
  7. Moyle G, DeJesus E, Boffito M, et al. Proof of activity with AMD11070, an orally bioavailable inhibitor of CXCR4-tropic HIV type 1. Clinical Infectious Diseases. 2009 Mar 15;48(6):​798-805.
  8. Rothenberger M, Wagner JE, Haase A, et al. Transplantation of CCR5∆32 homozygous umbilical cord blood in a child with acute lymphoblastic leukemia and perinatally acquired HIV infection. Open Forum Infectious Diseases. 2018 May 22;5(5):ofy090.
  9. Mueller KAL, Hanna DB, Ehinger E, et al. Loss of CXCR4 on non-classical monocytes in participants of the Women’s Interagency HIV Study (WIHS) with subclinical atherosclerosis. Cardiovascular Research. 2019; in press.
  10. Song H, Ou W, Feng Y, et al. Disparate impact on CD4 T cell count by two distinct HIV-1 phylogenetic clusters from the same clade. Proceedings of the National Academy of Sciences USA. 2019 Jan 2;116(1):239-244.
  11. Symons J, Vandekerckhove L, Hütter G, et al. Dependence on the CCR5 coreceptor for viral replication explains the lack of rebound of CXCR4-predicted HIV variants in the Berlin patient. Clinical Infectious Diseases. 2014 Aug 15;59(4):596-600.
  12. Henrich TJ, Hanhauser E, Hu Z, et al. Viremic control and viral coreceptor usage in two HIV-1-infected persons homozygous for CCR5 delta-32. AIDS. 2015 May 15;29(8):​867-76.
  13. Nedellec R, Herbeck JT, Hunt PW, et al. High-sequence diversity and rapid virus turnover contribute to higher rates of coreceptor switching in treatment-experienced subjects with HIV-1 viremia. AIDS Research and Human Retroviruses. 2017 Mar;33(3):234-245.
  14. Karlsson U, Antonsson L, Ljungberg B, et al. Dual R3R5 tropism characterizes cerebrospinal fluid HIV-1 isolates from individuals with high cerebrospinal fluid viral load. AIDS. 2012 Sep 10;26(14):1739-44.
  15. Karlsson U, Repits J, Antonsson L, et al. Reduced baseline sensitivity to maraviroc inhibition among R5 HIV-1 isolates from individuals with severe immunodeficiency. JAIDS. 2016 Mar 1;71(3):e79-82.

Do you work in HIV or hep C?
Complete a short survey to evaluate CATIE and enter a draw to win a $250 gift card.